Nitrogen containing heteroaromatics as factor Xa inhibitors

ABSTRACT

The present application describes nitrogen containing heteroaromatics and derivatives thereof of formula I: or pharmaceutically acceptable salt or prodrug forms thereof, wherein J is N or NH and D may be C(=NH)NH2, which are useful as inhibitors of factor Xa.

This application claims the benefit of U.S. Provisional Application No. 60/033,437, filed Dec. 23, 1996 and benefit of U.S. Provisional Application No. 60,050,304, filed Jun. 20, 1997.

FIELD OF THE INVENTION

This invention relates generally to nitrogen containing heteroaromatics which are inhibitors of trypsin-like serine protease enzymes, especially factor Xa, pharmaceutical compositions containing the same, and methods of using the same as anticoagulant agents for treatment and prevention of thromboembolic disorders.

BACKGROUND OF THE INVENTION

WO 95/18111 addresses fibrinogen receptor antagonists, containing basic and acidic termini, of the formula: ##STR2## wherein R¹ represents the basic termini, U is an alkylene or heteroatom linker, V may be a heterocycle, and the right hand portion of the molecule represents the acidic termini. The presently claimed compounds do not contain the acidic termini of WO 95/18111.

In U.S. Pat. No. 5,463,071, Himmelsbach et al depict cell aggregation inhibitors which are 5-membered heterocycles of the formula: ##STR3## wherein the heterocycle may be aromatic and groups A--B--C-- and F--E--D-- are attached to the ring system. A--B--C-- can be a wide variety of substituents including a basic group attached to an aromatic ring. The F--E--D-- group, however, would appear to be an acidic functionality which differs from the present invention. Furthermore, use of these compounds as inhibitors of factor Xa is not discussed.

Baker et al, in U.S. Pat. No. 5,317,103, discuss 5-HT₁ agonists which are indole substituted five-membered heteroaromatic compounds of the formula: ##STR4## wherein R¹ may be pyrrolidine or piperidine and A may be a basic group including amino and amidino. Baker et al, however, do not indicate that A can be a substituted ring system like that contained in the presently claimed heteroaromatics.

Baker et al, in WO 94/02477, discuss 5-HT₁ agonists which are imidazoles, triazoles, or tetrazoles of the formula: ##STR5## wherein R¹ represents a nitrogen containing ring system or a nitrogen substituted cyclobutane, and A may be a basic group including amino and amidino. Baker et al, however, do not indicate that A can be a substituted ring system like that contained in the presently claimed heteroaromatics.

Tidwell et al, in J. Med. Chem. 1978, 21(7), 613-623, describe a series of diarylamidine derivatives including 3,5-bis(4-amidinophenyl)pyrrole. This series of compounds was tested against thrombin, trypsin, and pancreatic kallikrein. The presently claimed invention does not include these types of compounds.

Activated factor Xa, whose major practical role is the generation of thrombin by the limited proteolysis of prothrombin, holds a central position that links the intrinsic and extrinsic activation mechanisms in the final common pathway of blood coagulation. The generation of thrombin, the final serine protease in the pathway to generate a fibrin clot, from its precursor is amplified by formation of prothrombinase complex (factor Xa, factor V, Ca²⁺ and phospholipid). Since it is calculated that one molecule of factor Xa can generate 138 molecules of thrombin (Elodi, S., Varadi, K.: Optimization of conditions for the catalytic effect of the factor IXa-factor VIII Complex: Probable role of the complex in the amplification of blood coagulation. Thromb. Res. 1979, 15, 617-629), inhibition of factor Xa may be more efficient than inactivation of thrombin in interrupting the blood coagulation system.

Therefore, efficacious and specific inhibitors of factor Xa are needed as potentially valuable therapeutic agents for the treatment of thromboembolic disorders. It is thus desirable to discover new factor Xa inhibitors.

SUMMARY OF THE INVENTION

Accordingly, one object of the present invention is to provide novel nitrogen containing aromatic heterocycles which are useful as factor Xa inhibitors or pharmaceutically acceptable salts or prodrugs thereof.

It is another object of the present invention to provide pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.

It is another object of the present invention to provide a method for treating thromboembolic disorders comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.

These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors' discovery that compounds of formula (I): ##STR6## or pharmaceutically acceptable salt or prodrug forms thereof, wherein A, B, D, E, G, J, M, R^(1a), R^(1b), s and m/z are defined below, are effective factor Xa inhibitors.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

[1] Thus, in a first embodiment, the present invention provides novel compounds of formula I: ##STR7## or a stereoisomer or pharmaceutically acceptable salt thereof, wherein; ring M contains, in addition to J, 0-3 N atoms, provided that if X contains 2 N atoms then R^(1b) is not present and if M contains 3 N atoms then R^(1a) and R^(1b) are not present;

J is N or NH;

D is selected from CN, C(═NR⁸)NR⁷ R⁹, NHC(═NR⁸)NR⁷ R⁹, NR⁸ CH(═NR⁷), C(O)NR⁷ R⁸, and (CR⁸ R⁹)_(t) NR⁷ R⁸, provided that D is substituted meta or para to G on E;

E is selected from phenyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, and piperidinyl substituted with 1 R;

alternatively, D--E--G together represent pyridyl substituted with 1 R;

R is selected from H, halogen, (CH₂)_(t) OR³, C₁₋₄ alkyl, OCF₃, and CF₃ ;

G is absent or is selected from NHCH₂, OCH₂, and SCH₂, provided that when s is 0, then G is attached to a carbon atom on ring M;

Z is selected from a C₁₋₄ alkylene, (CH₂)_(r) O(CH₂)_(r), (CH₂)_(r) NR³ (CH₂)_(r), (CH₂)_(r) C(O) (CH₂)_(r), (CH₂)_(r) C(O)O(CH₂)_(r), (CH₂)_(r) OC(O) (CH₂)_(r), (CH₂)_(r) C(O)NR³ (CH₂)_(r), (CH₂)_(r) NR³ C (O) (CH₂)_(r), (CH₂)_(r) OC (O)O(CH₂)_(r), (CH₂)_(r) OC (O)NR³ (CH₂)_(r), (CH₂)_(r) NR³ C(O)O(CH₂)_(r), (CH₂)_(r) NR³ C(O)NR³ (CH₂)_(r), (CH₂)_(r) S(O)_(p) (CH₂)_(r), (CH₂)_(r) SO₂ NR³ (CH₂)_(r), (CH₂)_(r) NR³ SO₂ (CH₂)_(r), and (CH₂)_(r) NR³ SO₂ NR³ (CH₂)_(r), provided that Z does not form a N--N, N--O, N--S, NCH₂ N, NCH₂ O, or NCH₂ S bond with ring M or group A;

R^(1a) and R^(1b) are independently absent or selected from --(CH₂)r--R^(1'), NCH₂ R^(1"), OCH₂ R^(1'), SCH₂ R^(1"), N(CH₂)₂ (CH₂)_(t) R^(1'), O(CH₂)₂ (CH₂)_(t) R^(1"), and S(CH₂)₂ (CH₂)_(t) R^(1'), or combined to form a 5-8 membered saturated, partially saturated or unsaturated ring substituted with 0-2 R⁴ and which contains from 0-2 heteroatoms selected from the group consisting of N, O, and S;

R^(1') is selected from H, C₁₋₃ alkyl, halo, (CF₂)_(r) CF₃, OR², NR² R^(2a), C(O)R^(2c), OC(O)R², (CF₂)_(r) CO₂ R^(2c), S(O)_(p) R2b, NR² (CH₂)_(r) OR², NR² C(O)R^(2b), NR² C(O)NHR2b, NR² C(O)₂ R^(2a), OC(O)NR^(2b), C(O)NR² R^(2a), SO₂ NR² R^(2a), NR² SO₂ R^(2b), C₃₋₆ carbocyclic residue substituted with 0-2 R⁴, and 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R⁴ ;

R¹ " is selected from H, C(O)R^(2b), C(O)NR² R^(2a), S(O)R^(2b), S(O)₂ R^(2b), and SO₂ NR² R^(2a) ;

R², at each occurrence, is selected from H, CF₃, C₁₋₆ alkyl, benzyl, C₃₋₆ carbocyclic residue substituted with 0-2 R^(4b), and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R^(4b) ;

R^(2a), at each occurrence, is selected from H, CF₃, C₁₋₆ alkyl, benzyl, C₃₋₆ carbocyclic residue substituted with 0-2 R^(4b), and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R^(4b) ;

R^(2b), at each occurrence, is selected from CF₃, C₁₋₄ alkoxy, C₁₋₆ alkyl, benzyl, C₃₋₆ carbocyclic residue substituted with 0-2 R^(4b), and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R^(4b) ;

R^(2c), at each occurrence, is selected from CF₃, C₁₋₄ alkoxy, C₁₋₆ alkyl, benzyl, C₃₋₆ carbocyclic residue substituted with 0-2 R^(4b), and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R^(4b) ;

alternatively, R² and R^(2a) combine to form a 5 or 6 membered saturated, partially saturated or unsaturated ring substituted with 0-2 R^(4b) which contains from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;

R³, at each occurrence, is selected from H, C₁₋₄ alkyl, and phenyl;

R^(3a), at each occurrence, is selected from H, C₁₋₄ alkyl, and phenyl;

A is selected from:

C₃₋₁₀ carbocyclic residue substituted with 0-2 R⁴, and

5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R⁴ ;

B is selected from:

X--Y, NR² R^(2a), C (═NR²) NR² R^(2a), NR² C (═NR²) NR² R^(2a), C₃₋₁₀ carbocyclic residue substituted with 0-2 R^(4a), and

5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R^(4a) ;

X is selected from C₁₋₄ alkylene, --CR² (CR² R^(2b)) (CH₂)_(t) --, --C(O)--, --C(═NR)--, --CR² (NR¹ "R²)--, --CR² (OR²)--, --CR² (SR²)--, --C(O)CR² R^(2a) --, --CR² R^(2a) C(O), --S(O)_(p) --, --S(O)_(p) CR² R^(2a) --, --CR² R^(2a) S(O)_(p) --, --S(O)₂ NR² --, --NR² S(O)₂ --, --NR² S(O)₂ CR² R^(2a) --, --CR² R^(2a) S(O)₂ NR² --, --NR² S(O)₂ NR² --, --C(O)NR² --, --NR² C(O)--, --C(O)NR² CR² R^(2a) --, --NR² C(O)CR² R^(2a) --, --CR² R^(2a) C(O)NR² --, --CR² R^(2a) NR² C(O)--, --NR² C(O)O--, --OC(O)NR² --, --NR² C(O)NR² --, --NR² --, --NR² CR² R^(2a) --, --CR² R^(2a) NR² --, O, --CR² R^(2a) O--, and --OCR² R^(2a) --;

Y is selected from:

(CH₂)_(r) NR² R^(2a), provided that X--Y do not form a N--N, O--N, or S--N bond,

C₃₋₁₀ carbocyclic residue substituted with 0-2 R^(4a), and

5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R^(4a) ;

R⁴, at each occurrence, is selected from ═O, (CH₂)_(r) OR², halo, C₁₋₄ alkyl, --CN, NO₂, (CH₂)_(r) NR² R^(2a), (CH₂)_(r) C(O)R^(2b), NR² C(O)R^(2b), C(O)NR² R^(2a), NR² C(O)NR² R^(2a), CH(═NR²)NR² R^(2a), NHC(═NR²)NR² R^(2a), SO₂ NR² R^(2a), NR² SO₂ NR² R^(2a), NR² SO₂ --C₁₋₄ alkyl, NR² SO₂ R⁵, S(O)_(p) R⁵, (CF₂)_(r) CF₃, NCH₂ R^(1"), OCH₂ R^(1"), SCH₂ R^(1"), N(CH₂)₂ (CH₂)_(t) R¹ ', O(CH₂)₂ (CH₂)_(t) R¹ ', and S(CH₂)₂ (CH₂)_(t) R^(1'),

alternatively, one R⁴ is a 5-6 membered aromatic heterocycle containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;

R^(4a), at each occurrence, is selected from ═O, (CH₂)_(r) OR², halo, C₁₋₄ alkyl, --CN, NO₂, (CH₂)_(r) NR² R^(2a), (CH₂)_(r) C(O)R^(2b), NR² C(O)R^(2b), C(O)NR² R^(2a), NR² C(O)NR² R^(2a), CH(═NR²)NR² R^(2a), NHC(═NR²)NR² R^(2a), SO₂ NR² R^(2a), NR² SO₂ NR² R^(2a), NR² SO₂ --C₁₋₄ alkyl, NR² SO₂ R⁵, S(O)_(p) R⁵, and (CF₂)_(r) CF₃ ;

alternatively, one R^(4a) is a 5-6 membered aromatic heterocycle containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-1 R⁵ ;

R^(4b), at each occurrence, is selected from ═O, (CH₂)_(r) OR³, halo, C₁₋₄ alkyl, --CN, NO₂, (CH₂)_(r) NR³ R^(3a), (CH₂)_(r) C(O)R³, NR³ C(O)R^(3a), C(O)NR³ R^(3a), NR³ C(O)NR³ R^(3a), CH(═NR³)NR³ R^(3a), NH³ C (═NR³)NR³ R^(3a), SO₂ NR³ R^(3a), NR³ SO₂ NR³ R^(3a), NR³ SO₂ --C₁₋₄ alkyl, NR³ SO₂ CF₃, NR³ SO₂ -phenyl, S(O)_(p) CF₃, S(O)_(p) --C₁₋₄ alkyl, S(O)_(p) -phenyl, and (CF₂)_(r) CF₃ ;

R₅, at each occurrence, is selected from CF₃, C₁₋₆ alkyl, phenyl substituted with 0-2 R⁶, and benzyl substituted with 0-2 R⁶ ;

R⁶, at each occurrence, is selected from H, OH, (CH₂)_(r) OR², halo, C₁₋₄ alkyl, CN, NO₂, (CH₂)_(r) NR² R^(2a), (CH₂)_(r) C(O)R^(2b), NR² C(O)R2b, NR² C(O)NR² R^(2a), CH(═NH)NH₂, NHC(═NH)NH₂, SO₂ NR² R^(2a), NR² SO₂ NR² R^(2a), and NR² SO₂ C₁₋₄ alkyl;

R⁷, at each occurrence, is selected from H, OH, C₁₋₆ alkyl, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxy, C₁₋₄ alkoxycarbonyl, (CH₂)_(n) -phenyl, C₆₋₁₀ aryloxy, C₆₋₁₀ aryloxycarbonyl, C₆₋₁₀ arylmethylcarbonyl, C₁₋₄ alkylcarbonyloxy C₁₋₄ alkoxycarbonyl, C₆₋₁₀ arylcarbonyloxy C₁₋₄ alkoxycarbonyl, C₁₋₆ alkylaminocarbonyl, phenylaminocarbonyl, and phenyl C₁₋₄ alkoxycarbonyl;

R⁸, at each occurrence, is selected from H, C₁₋₆ alkyl and (CH₂)_(n) -phenyl;

alternatively, R⁷ and R⁸ combine to form a 5 or 6 membered saturated, ring which contains from 0-additional heteroatoms selected from the group consisting of N, O, and S;

R⁹, at each occurrence, is selected from H, C₁₋₆ alkyl and (CH₂)_(n) -phenyl;

n, at each occurrence, is selected from 0, 1, 2, and 3;

m, at each occurrence, is selected from 0, 1, and 2;

p, at each occurrence, is selected from 0, 1, and 2;

r, at each occurrence, is selected from 0, 1, 2, and 3;

s, at each occurrence, is selected from 0, 1, and 2; and,

t, at each occurrence, is selected from 0 and 1;

provided that D--E--G--(CH₂)_(s) -- and --Z--A--B are not both benzamidines.

[2] In a preferred embodiment, the present invention provides novel compounds of formulae Ia-Ih: ##STR8## wherein, groups D--E-- and --Z--A--B are attached to adjacent atoms on the ring;

Z is selected from a CH₂ O, OCH₂, CH₂ NH, NHCH₂, C(O), CH₂ C(O), C(O)CH₂, NHC(O), C(O)NH, CH₂ S(O)₂, S(O)₂ (CH₂), SO₂ NH, and NHSO₂, provided that Z does not form a N--N, N--O, NCH₂ N, or NCH₂ O bond with ring M or group A;

A is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R⁴ ;

phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, benzofuranyl, benzothiofuranyl, indolyl, benzimidazolyl, benzoxazolyl, benzthiazolyl, indazolyl, benzisoxazolyl, benzisothiazolyl, and isoindazolyl;

B is selected from: Y, X--Y, NR² R^(2a), C(═NR²)NR² R^(2a), and NR² C (═NR²) NR² R^(2a) ;

X is selected from C₁₋₄ alkylene, --C(O)--, --C(═NR)--, --CR² (NR² R^(2a))--, --C(O)CR² R^(2a) --, --CR² R^(2a) C(O), --C(O)NR² --, --NR² C(O)--, --C(O)NR² CR² R^(2a) --, --NR² C(O)CR² R^(2a) --, --CR² R^(2a) C(O)NR² --, --CR² R^(2a) NR² C(O)--, --NR² C(O)NR² --, --NR2--, --NR² CR² R^(2a) --, --CR² R^(2a) NR² --, O, --CR² R^(2a) O--, and --OCR² R^(2a) --;

Y is NR² R^(2a), provided that X--Y do not form a N--N or O--N bond;

alternatively, Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R^(4a) ;

cylcopropyl, cyclopentyl, cyclohexyl, phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, isoxazolinyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazoolyl, benzofuranyl, benzothiofuranyl, indolyl, benzimidazolyl, benzoxazolyl, benzthiazolyl, indazolyl, benzisoxazolyl, benzisothiazolyl, and isoindazolyl;

alternatively, Y is selected from the following bicyclic heteroaryl ring systems: ##STR9## K is selected from O, S, NH, and N. [3] In a more preferred embodiment, the present invention provides novel compounds of formulae IIa-IIf: ##STR10## wherein; Z is selected from a C(O), CH₂ C(O), C(O)CH₂, NHC(O), C(O)NH, C(O)N(CH₃), CH₂ S(O)₂, S(O)₂ (CH₂), SO₂ NH, and NHSO₂, provided that Z does not form a N--N or NCH₂ N bond with ring M or group A.

[4] In an even more preferred embodiment, the present invention provides novel compounds of formulae IIa-IIf, wherein;

E is phenyl substituted with R or 2-pyridyl substituted with R;

D is selected from NH₂, C(O)NH₂, C (═NH)NH₂, CH₂ NH₂, CH₂ NHCH₃, CH(CH₃)NH₂, and C(CH₃)₂ NH₂, provided that D is substituted meta or para to ring M on E; and,

R is selected from H, OCH₃, Cl, and F.

[5] In a further preferred embodiment, the present invention provides novel compounds of formulae IIa-IIf, wherein;

D--E is selected from 3-aminophenyl, 3-amidinophenyl, 3-aminomethylphenyl, 3-aminocarbonylphenyl, 3-(methylaminomethyl)phenyl, 3-(1-aminoethyl)phenyl, 3-(2-amino-2-propyl)phenyl, 4-chloro-3-aminophenyl, 4-chloro-3-amidinophenyl, 4-chloro-3-aminomethylphenyl, 4-chloro-3-(methylaminomethyl)phenyl, 4-fluoro-3-aminophenyl, 4-fluoro-3-amidinophenyl, 4-fluoro-3-aminomethylphenyl, 4-fluoro-3-(methylaminomethyl)phenyl, 6-aminopyrid-2-yl, 6-amidinopyrid-2-yl, 6-aminomethylpyrid-2-yl, 6-aminocarbonylpyrid-2-yl, 6-(methylaminomethyl)pyrid-2-yl, 6-(1-aminoethyl)pyrid-2-yl, and 6-(2-amino-2-propyl)pyrid-2-yl.

[6] In another even more preferred embodiment, the present invention provides novel compounds of formulae IIa-IIf, wherein;

Z is C(O)CH₂ and CONH, provided that Z does not form a N--N bond with group A;

A is selected from phenyl, pyridyl, and pyrimidyl, and is substituted with 0-2 R⁴ ; and,

B is selected from X--Y, phenyl, pyrrolidino, morpholino, 1,2,3-triazolyl, and imidazolyl, and is substituted with 0--R^(4a) ;

R⁴, at each occurrence, is selected from OH, (CH₂)_(r) OR², halo, C₁₋₄ alkyl, (CH₂)_(r) NR² R^(2a), and (CF₂)_(r) CF₃ ;

R^(4a) is selected from C₁₋₄ alkyl, CF₃, S(O)_(p) R⁵, SO₂ NR² R^(2a), and 1-CF₃ -tetrazol-2-yl;

R⁵, at each occurrence, is selected from CF₃, C₁₋₆ alkyl, phenyl, and benzyl;

X is CH₂ or C(O); and,

Y is selected from pyrrolidino and morpholino.

[7] In another further preferred embodiment, the present invention provides novel compounds of formulae IIa-IIf, wherein;

A is selected from the group: phenyl, 2-pyridyl, 3-pyridyl, 2-pyrimidyl, 2-Cl-phenyl, 3-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 2-methylphenyl, 2-aminophenyl, and 2-methoxyphenyl; and,

B is selected from the group: 2-CF₃ -phenyl, 2-(aminosulfonyl)phenyl, 2-(methylaminosulfonyl)phenyl, 2-(dimethylaminosulfonyl)phenyl, 1-pyrrolidinocarbonyl, 2-(methylsulfonyl)phenyl, 4-morpholino, 2-(1'-CF₃ -tetrazol-2-yl)phenyl, 4-morpholinocarbonyl, 2-methyl-1-imidazolyl, 5-methyl-1-imidazolyl, 2-methylsulfonyl-1-imidazolyl and, 5-methyl-1,2,3-triazolyl.

[8 ] In another even more preferred embodiment, the present invention provides novel compounds of formulae IIa-IIf, wherein;

E is phenyl substituted with R or 2-pyridyl substituted with R;

D is selected from NH₂, C(O)NH₂, C(═NH)NH₂, CH₂ NH₂, CH₂ NHCH₃, CH(CH₃)NH₂, and C(CH₃)₂ NH₂, provided that D is substituted meta or para to ring M on E; and,

R is selected from H, OCH₃, Cl, and F;

Z is C(O)CH₂ and CONH, provided that Z does not form a N--N bond with group A;

A is selected from phenyl, pyridyl, and pyrimidyl, and is substituted with 0-2 R⁴ ; and,

B is selected from X--Y, phenyl, pyrrolidino, morpholino, 1,2,3-triazolyl, and imidazolyl, and is substituted with 0-1 R^(4a) ;

R⁴, at each occurrence, is selected from OH, (CH₂)_(r) OR², halo, C₁₋₄ alkyl, (CH₂)_(r) NR² R^(2a), and (CF₂)_(r) CF₃ ;

R^(4a) is selected from C₁₋₄ alkyl, CF₃, S(O)_(p) R⁵, SO₂ NR² R^(2a), and 1-CF₃ -tetrazol-2-yl;

R⁵, at each occurrence, is selected from CF₃, C₁₋₆ alkyl, phenyl, and benzyl;

X is CH₂ or C(O); and,

Y is selected from pyrrolidino and morpholino.

[9] In another further preferred embodiment, the present invention provides novel compounds of formulae IIa-IIf, wherein;

D--E is selected from 3-aminophenyl, 3-amidinophenyl, 3-aminomethylphenyl, 3-aminocarbonylphenyl, 3-(methylaminomethyl)phenyl, 3-(1-aminoethyl)phenyl, 3-(2-amino-2-propyl)phenyl, 4-chloro-3-aminophenyl, 4-chloro-3-amidinophenyl, 4-chloro-3-aminomethylphenyl, 4-chloro-3-(methylaminomethyl)phenyl, 4-fluoro-3-aminophenyl, 4-fluoro-3-amidinophenyl, 4-fluoro-3-aminomethylphenyl, 4-fluoro-3-(methylaminomethyl)phenyl, 6-aminopyrid-2-yl, 6-amidinopyrid-2-yl, 6-aminomethylpyrid-2-yl, 6-aminocarbonylpyrid-2-yl, 6-(methylaminomethyl)pyrid-2-yl, 6-(l-aminoethyl)pyrid-2-yl, 6-(2-amino-2-propyl)pyrid-2-yl;

A is selected from the group: phenyl, 2-pyridyl, 3-pyridyl, 2-pyrimidyl, 2-Cl-phenyl, 3-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 2-methylphenyl, 2-aminophenyl, and 2-methoxyphenyl; and,

B is selected from the group: 2-CF₃ -phenyl, 2-(aminosulfonyl)phenyl, 2-(methylaminosulfonyl)phenyl, 2-(dimethylaminosulfonyl)phenyl, 1-pyrrolidinocarbonyl, 2-(methylsulfonyl)phenyl, 4-morpholino, 2-(1'-CF₃ -tetrazol-2-yl)phenyl, 4-morpholinocarbonyl, 2-methyl-1-imidazolyl, 5-methyl-1-imidazolyl, 2-methylsulfonyl-1-imidazolyl and, 5-methyl-1,2,3-triazolyl.

[10] In a still further preferred embodiment, the present invention provides a novel compound of formula IIa.

[11] In another still further preferred embodiment, the present invention provides a novel compound of formula IIb.

[12] In another still further preferred embodiment, the present invention provides a novel compound of formula IIc.

[13] In another still further preferred embodiment, the present invention provides a novel compound of formula IId.

[14] In another still further preferred embodiment, the present invention provides a novel compound of formula IIe.

[15] In another still further preferred embodiment, the present invention provides a novel compound of formula IIf.

[16] In another even more preferred embodiment, the present invention provides novel compounds of formulae IIa-IIf, wherein;

D is selected from C(═NR⁸)NR⁷ R⁹, C(O)NR⁷ R⁸, NR⁷ R⁸, and CH₂ NR⁷ R⁸, provided that D is substituted meta or para to ring M on E;

E is phenyl substituted with R or pyridyl substituted with R;

R is selected from H, Cl, F, OR³, CH₃, CH₂ CH₃, OCF₃, and CF₃ ;

Z is selected from C(O), CH₂ C(O), C(O)CH₂, NHC(O), and C(O)NH, provided that Z does not form a N--N bond with ring M or group A;

R^(1a) and R^(1b) are independently absent or selected from --(CH₂)_(r) --R¹ ', NCH₂ R¹ ", OCH₂ R¹ ", SCH₂ R¹ ", N(CH₂)₂ (CH₂)_(t) R¹ ', O(CH₂)₂ (CH₂)_(t) R¹ ', and S(CH₂)₂ (CH₂)_(t) R¹ ', or combined to form a 5-8 membered saturated, partially saturated or unsaturated ring substituted with 0-2 R⁴ and which contains from 0-2 heteroatoms selected from the group consisting of N, O, and S;

R¹ ', at each occurrence, is selected from H, C₁₋₃ alkyl, halo, (CF₂)_(r) CF₃, OR², NR² R^(2a), C(O)R^(2c), (CF₂)_(r) CO₂ R^(2c), S(O)_(p) R^(2b), NR² (CH₂)_(r) OR², NR² C(O)R^(2b), NR² C(0)₂ R^(2b), C(O)NR² R^(2a), SO₂ NR² R^(2a), and NR² SO₂ R^(2b) ;

A is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R⁴ ;

phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, and imidazolyl;

B is selected from: Y, X--Y, NR² R^(2a), C(═NR²)NR² R^(2a), and NR² C (═NR²) NR² R^(2a) ;

X is selected from CH₂, --CR² (CR² R^(2b)) (CH₂)t--, --C(O)--, --C(═NR)--, --CH(NR² R^(2a))--, --C(O)NR² --, --NR² C(O)--, --NR² C(O)NR² --, --NR² --, and O;

Y is NR² R^(2a), provided that X--Y do not form a N--N or O--N bond;

alternatively, Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R^(4a) ;

phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, isoxazolinyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, and 1,3,4-triazolyl;

R⁴, at each occurrence, is selected from ═O, OH, Cl, F, C₁₋₄ alkyl, (CH₂)_(r) NR² R^(2a), (CH₂)_(r) C(O)R^(2b), NR² C(O)R^(2b), C(O)NR² R^(2a), CH(═NH)NH₂, NHC(═NH)NH₂, SO₂ NR² R^(2a), NR² SO₂ --C₁₋₄ alkyl, NR² SO₂ R⁵, S(O)_(p) R⁵, and (CF₂)_(r) CF₃ ;

R^(4a), at each occurrence, is selected from ═O, OH, Cl, F, C1-4 alkyl, (CH₂)_(r) NR² R^(2a), (CH₂)_(r) C(O)R^(2b), NR² C(O)R2b, C(O)NR² R^(2a), CH(═NH)NH₂, NHC(═NH)NH₂, SO₂ NR² R^(2a), NR² SO₂ --C₁₋₄ alkyl, NR² SO₂ R⁵, S(O)_(p) R⁵, (CF₂)_(r) CF₃, and 1-CF₃ -tetrazol-2-yl;

R⁵, at each occurrence, is selected from CF₃, C₁₋₆ alkyl, phenyl substituted with 0-2 R⁶, and benzyl substituted with 0-2 R⁶ ;

R⁶, at each occurrence, is selected from H, ═O, OH, OR², Cl, F, CH₃, CN, NO₂, (CH₂)_(r) NR² R^(2a), (CH₂)_(r) C(O)R^(2b), NR² C(O)R^(2b), CH (═NH) NH₂, NHC (═NH) NH₂, and SO₂ NR² R^(2a) ;

R⁷, at each occurrence, is selected from H, OH, C1-6 alkyl, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxy, C₁₋₄ alkoxycarbonyl, benzyl, C₆₋₁₀ aryloxy, C₆₋₁₀ aryloxycarbonyl, C₆₋₁₀ arylmethylcarbonyl, C₁₋₄ alkylcarbonyloxy C₁₋₄ alkoxycarbonyl, C₆₋₁₀ arylcarbonyloxy C₁₋₄ alkoxycarbonyl, C₁₋₆ alkylaminocarbonyl, phenylaminocarbonyl, and phenyl C₁₋₄ alkoxycarbonyl;

R⁸, at each occurrence, is selected from H, C₁₋₆ alkyl and benzyl; and

alternatively, R⁷ and R⁸ combine to form a morpholino group; and,

R⁹, at each occurrence, is selected from H, C₁₋₆ alkyl and benzyl.

[17] In a another further preferred embodiment, the present invention provides novel compounds of formulae IIa-IIf, wherein;

E is phenyl substituted with R or 2-pyridyl substituted with R;

R is selected from H, Cl, F, OCH₃, CH₃, OCF₃, and CF₃ ;

Z is selected from a C(O)CH₂ and C(O)NH, provided that Z does not form a N--N bond with group A;

R^(1a) is selected from H, CH₃, CH₂ CH₃, Cl, F, CF₃, OCH₃, NR² R^(2a), S(O)_(p) R^(2b), CH₂ S(O)_(p) R^(2b), CH₂ NR² S(O)_(p) R^(2b), C(O)R^(2c), CH₂ C(O)R^(2c), C(O)NR² R^(2a), and SO₂ NR² R^(2a) ;

R^(1b) is selected from H, CH₃, CH₂ CH₃, Cl, F, CF₃, OCH₃, NR² R^(2a), S(O) _(p) R^(2b), CH₂ S(O)_(p) R^(2b), CH₂ NR² S(O)_(p) R^(2b), C(O))R^(2c), CH₂ C(O)R^(2c), C(O)NR² R^(2a), and SO₂ NR² R^(2a) ;

A is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R⁴ ;

phenyl, pyridyl, pyrimidyl, furanyl, thiophenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, and imidazolyl;

B is selected from: Y and X--Y;

X is selected from CH₂, --CR² (CR² R^(2b))--, --C(O)--, --C(═NR)--, --CH(NR² R^(2a))--, --C(O)NR² --, --NR² C(O)--, --NR² C(O)NR² --, --NR2--, and O;

Y is NR² R^(2a), provided that X--Y do not form a N--N or O--N bond;

alternatively, Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R^(4a) ;

phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, isoxazolinyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, and 1,3,4-triazolyl;

R², at each occurrence, is selected from H, CF₃, CH₃, benzyl, and phenyl;

R^(2a), at each occurrence, is selected from H, CF₃, CH₃, benzyl, and phenyl;

R^(2b), at each occurrence, is selected from CF₃, OCH₃, CH₃, benzyl, and phenyl;

R^(2c), at each occurrence, is selected from CF₃, OH, OCH₃, CH₃, benzyl, and phenyl;

alternatively, R² and R^(2a) combine to form a 5 or 6 membered saturated, partially unsaturated, or unsaturated ring which contains from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;

R³, at each occurrence, is selected from H, CH₃, CH₂ CH₃, and phenyl;

R^(3a), at each occurrence, is selected from H, CH₃, CH₂ CH₃, and phenyl;

R⁴, at each occurrence, is selected from OH, Cl, F, CH₃, CH₂ CH₃, NR² R^(2a), CH₂ NR² R^(2a), C(O)R^(2b), NR² C(O)R^(2b), C(O)NR² R^(2a), and CF₃ ;

R^(4a), at each occurrence, is selected from OH, Cl, F, CH₃, CH₂ CH₃, NR² R^(2a), CH₂ NR² R^(2a), C (O) R2b, C (O) NR² R^(2a), SO₂ NR² R^(2a), S(O)_(p) R⁵, CF₃, and 1-CF₃ -tetrazol-2-yl;

R⁵, at each occurrence, is selected from CF₃, C1-6 alkyl, phenyl substituted with 0-2 R⁶, and benzyl substituted with 1 R⁶ ;

R⁶, at each occurrence, is selected from H, OH, OCH₃, Cl, F, CH₃, CN, NO₂, NR² R^(2a), CH₂ NR² R^(2a), and SO₂ NR² R^(2a) ;

R⁷, at each occurrence, is selected from H, OH, C₁₋₃ alkyl, C₁₋₃ alkylcarbonyl, C₁₋₃ alkoxy, C₁₋₄ alkoxycarbonyl, benzyl, phenoxy, phenoxycarbonyl, benzylcarbonyl, C₁₋₄ alkylcarbonyloxy C₁₋₄ alkoxycarbonyl, phenylcarbonyloxy C₁₋₄ alkoxycarbonyl, C₁₋₆ alkylaminocarbonyl, phenylaminocarbonyl, and phenyl C₁₋₄ alkoxycarbonyl;

R⁸, at each occurrence, is selected from H, CH₃, and benzyl; and,

alternatively, R⁷ and R⁸ combine to form a morpholino group;

R⁹, at each occurrence, is selected from H, CH₃, and benzyl.

[18] In a another still further preferred embodiment, the present invention provides novel compounds of formulae IIa-IIf, wherein;

R^(1a) is absent or is selected from H, CH₃, CH₂ CH₃, Cl, F, CF₃, OCH₃, NR² R^(2a), S(O)_(p) R^(2b), C(O)NR² R^(2a), CH₂ S(O)_(p) R^(2b), CH₂ NR² S(O)_(p) R^(2b), C(O)R^(2c), CH₂ C(O)R^(2c), and SO₂ NR² R^(2a) ;

R^(1b) is absent or is selected from H, CH₃, CH₂ CH₃, Cl, F, CF₃, OCH₃, NR² R^(2a), S(O)_(p) R^(2b), C(O)NR² R^(2a), CH₂ S(O)_(p) R^(2b), CH₂ NR² S(O)_(p) R^(2b), C(O)R^(2b), CH₂ C(O)R^(2b), and SO₂ NR² R^(2a) ;

A is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R⁴ ;

phenyl, pyridyl, and pyrimidyl;

B is selected from: Y and X--Y;

X is selected from --C(O)-- and O;

Y is NR² R^(2a), provided that X--Y do not form a O--N bond;

alternatively, Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R^(4a) ;

phenyl, piperazinyl, pyridyl, pyrimidyl, morpholinyl, pyrrolidinyl, imidazolyl, and 1,2,3-triazolyl;

R², at each occurrence, is selected from H, CF₃, CH₃, benzyl, and phenyl;

R^(2a), at each occurrence, is selected from H, CF₃, CH₃, benzyl, and phenyl;

R^(2b), at each occurrence, is selected from CF₃, OCH₃, CH₃, benzyl, and phenyl;

R^(2c), at each occurrence, is selected from CF₃, OH, OCH3, CH₃, benzyl, and phenyl;

alternatively, R² and R^(2a) combine to form a ring system selected from pyrrolidinyl, piperazinyl and morpholino;

R⁴, at each occurrence, is selected from Cl, F, CH₃, NR² R^(2a), and CF₃ ;

R^(4a), at each occurrence, is selected from Cl, F, CH₃, SO₂ NR² R^(2a), S(O)_(p) R⁵, and CF₃ ; and,

R⁵, at each occurrence, is selected from CF₃ and CH₃.

[19] Specifically preferred compounds of the present invention are selected from the group:

1-(3-amidinophenyl)-2-[[(2'-aminosulfonyl-[1,1']-biphen-4-yl)-aminocarbonyl]pyrrole;

1-(3-amidinophenyl)-2-[[(2'-tert-butylaminosulfonyl-[1,1']-biphen-4-yl)-aminocarbonyl]pyrrole;

1-(3-amidinophenyl)-2-[[(2'-aminosulfonyl-[1,1']-biphen-4-yl)-aminocarbonyl]-4-bromopyrrole;

1-(3-amidinophenyl)-2-[[5-(2'-aminosulfonylphen-1-yl) pyridin-2-yl]-aminocarbonyl]pyrrole;

1-benzyl-3-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-4-(3-amidinophenyl)pyrrole;

1-benzyl-3-[(2'-tert-butylaminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-4-(3-amidinophenyl)pyrrole;

1-(3-amidinophenyl)-4-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-imidazole;

1-(3-amidinophenyl)-4-[(2'-tert-butylaminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-imidazole;

1-(3-amidinophenyl)-2-[(1'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-imidazole;

1-(3-amidinophenyl)-3-methyl-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole;

1-(3-amidinophenyl)-3-methyl-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)carbonylamino]pyrazole;

1-(3-amidinophenyl)-3-methyl-5-(2'-(5"-CF₃ -tetrazolyl)-[1,1']-biphen-4-yl)aminocarbonyl)pyrazole;

1-(3-amidinophenyl)-5-[(2¹ -aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-4-chloro-3-methyl-pyrazole;

1-(3-amidinophenyl)-5-((2'-t-butylaminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl)-3-trifluoromethyl-pyrazole;

1-(3-amidinophenyl)-4-methoxy-5-((2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl)-3-trifluoromethyl-pyrazole;

1-(3-amidinophenyl)-3-methyl-5-(4'-(imidazol-1-yl-phenyl)aminocarbonyl)pyrazole;

1-(3-amidinophenyl)-3-methyl-5-[(4'-(2"-sulfonylmethyl)phenoxyphenyl)aminocarbonyl]pyrazole;

1-(3-amidinophenyl)-3-methyl-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)methylcarbonylpyrazole;

1-(3-amidinophenyl)-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-1,2,3-triazole;

1-(3-amidinophenyl)-5-((2'-trifluoromethyl-[1,1']-biphen-4-yl)aminocarbonyl)tetrazole;

1-(3-amidinophenyl)-5-((2'-aminosulfonyl-3-chloro-[1,1']-biphen-4-yl)methylthio)tetrazole;

1-(3-amidinophenyl)-5-[(2'-aminosulfonyl-3-chloro-[1,1']-biphen-4-yl)methylsulfoxide]tetrazole;

1-(3-amidinophenyl)-5-[(2'-aminosulfonyl-3-chloro-[1,1]-biphen-4-yl)methylsulfonyl]tetrazole;

1-(3-amidinophenyl)-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]tetrazole;

1-(3-amidinophenyl)-3-methyl-2-[[5-(2'-aminosulfonylphenyl-1-yl)pyridin-2-yl]-aminocarbonyl]pyrazole;

1-(3-amidinophenyl)-3-methyl-2-[[5-(2'-aminosulfonylphenyl-1-yl)pyrimidin-2-yl]-aminocarbonyl]pyrazole;

1-(3-amidinophenyl)-3-methyl-5-[(2'-aminosulfonyl-2-chloro-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole;

1-(3-amidinophenyl)-3-methyl-5-[(2'-aminosulfonyl-2-fluoro-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole;

1-(3-amidinophenyl)-3-methyl-5-[(2'-aminosulfonyl-4'-fluoro-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole;

1-(3-amidinophenyl)-3-methyl-5-[(2'-trifluoromethyl-[1,1]-biphen-4-yl)aminocarbonyl]pyrazole;

1-(3-amidinophenyl)-3-methyl-5-[(3-chloro-2'-trifluoromethyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole;

1-(3-amidinophenyl)-3-methyl-5-[(3-fluoro-2'-trifluoromethyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole;

1-(3-amidinophenyl)-3-methyl-2-[[5-(2'-trifluoromethylphenyl-1-yl)pyridin-2-yl]-aminocarbonyl]pyrazole;

1-(3-amidinophenyl)-3-methyl-5-[(2'-fluoro-[1,1]-biphen-4-yl)aminocarbonyl]pyrazole;

1-(3-amidinophenyl)-3-methyl-5-[(3-chloro-2'-fluoro-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole;

1-(3-amidinophenyl)-3-methyl-5-[(2'-methylsulfonyl-[1,1]'-biphen-4-yl)aminocarbonyl]pyrazole;

1-(3-amidinophenyl)-3-methyl-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)(N'-methyl)aminocarbonyl]pyrazole;

1-(3-amidinophenyl)-3-n-butyl-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole;

1-(3-amidinophenyl)-3-n-butyl-5-[((23-aminosulfonylphenyl-1-yl)pyridin-2-yl)-aminocarbonyl]pyrazole;

1-(3-amidinophenyl)-3-n-butyl-5-[((2'-trifluoromethylphenyl-1-yl)pyridin-2-yl)-aminocarbonyl]pyrazole;

1-(3-amidinophenyl)-5-[(2'-methylsulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-trifluoromethyl-pyrazole;

1-(3-amidinophenyl)-5-[(2'-trifluoromethyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-trifluoromethyl-pyrazole;

1-(3-amidinophenyl)-4-methoxy-5-((2'-trifluoromethyl-[1,1']-biphen-4-yl)aminocarbonyl)-3-trifluoromethyl-pyrazole;

1-(3-amidinophenyl)-3-methyl-5-[(4-trifluoromethylphenyl)aminocarbonylpyrazole;

1-(3-amidinophenyl)-4-methyl-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-imidazole;

1-(3-amidinophenyl)-5-[((2'-aminosulfonylphenyl-1-yl)pyridin-2-yl)-aminocarbonyl]-1,2,3-triazole;

1-(3-amidinophenyl)-5-[(2'-trifluoromethyl-[1,1]-biphen-4-yl)aminocarbonyl]-1,2,3-triazole;

1-(3-amidinophenyl)-5-[(2'-aminosulfonyl-[1,1]-biphen-4-yl)aminocarbonyl]-3-trifluoromethyl-1,2,4-triazole;

3-methyl-1-(3-amidinophenyl)-5-(4'-(4"-chlorophenyl)thiazol-2'-yl)aminocarbonyl)pyrazole;

1-(3-amidino)phenyl-3-methyl-5-[(2'-trifluoromethylsulfide-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole;

1-(3-amidino)phenyl-3-methyl-5-[(2'-trifluoromethylsulfoxide-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole;

1-(3-amidino)phenyl-3-methyl-5-[(2'-trifluoromethylsulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole;

1-(3-amidino)phenyl-3-methyl-5-[4'-(carboxymethyl)phenylaminocarbonyl]pyrazole;

1-(3-amidino)phenyl-3-methyl-5-[4'-(N,N-dimethylaminocarbonyl)phenylaminocarbonyl]pyrazole;

1-(3-amidino)phenyl-3-methyl-5-[4'-(N,N-dimethylaminosulfonyl)phenylaminocarbonyl]pyrazole;

1-(3-amidino)phenyl-3-methyl-5-[(4'-tert-butylaminosulfonylphenyl)aminocarbonyl]pyrazole;

1-(3-amidino)phenyl-3-methyl-5-[(4'-aminosulfonylphenyl)aminocarbonyl]pyrazole;

1-(3-amidino)phenyl-3-methyl-5-[(4'-trifluoromethylphenyl)-aminocarbonyl]pyrazole;

1-(3-amidino)phenyl-3-methyl-5-[(4'-benzylsulfonylpiperidyl)-aminocarbonyl]pyrazole;

1-(3-amidinophenyl)-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)-N-methylaminocarbonyl]-3-methyl-pyrazole;

1-(3-amidinophenyl)-5-[(4'-fluoro-[1,1]-biphen-4-yl)-aminocarbonyl]-3-methyl-pyrazole;

1-(3-amidinophenyl)-5-[[5 (2'-aminosulfonylphenyl)pyridin-2-yl]aminocarbonyl]-3-methyl-pyrazole;

1-(3-cyanophenyl)-5-[[5-(2'-aminosulfonylphenyl) pyridin-2-yl]aminocarbonyl]-3-methyl-pyrazole;

1-(3-amidinophenyl)-5-[(2'-trifluoromethyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-methyl-pyrazole;

1-(3-aminocarbonylphenyl)-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-methyl-pyrazole;

1-(3-amidinophenyl)-5-[(2'-aminosulfonyl)-3-chloro-[1,1']-biphen-4-yl)aminocarbonyl]-3-methyl-pyrazole;

1-(3-amidinophenyl)-5-[(2'-trifluoromethyl)-3-chloro-[1,1']-biphen-4-yl)aminocarbonyl]-3-methylpyrazole;

1-(3-amidinophenyl)-5-[(2'-aminosulfonyl-[1,1]-biphen-4-yl)aminocarbonyl]-3-n-butylpyrazole;

1-(3-amidinophenyl)-5-[(2'-trifluoromethyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-n-butylpyrazole;

1-(3-amidinophenyl)-5-[[5-(2'-aminosulfonylphenyl)pyridin-2-yl1aminocarbonyl]-3-n-butylpyrazole;

1-(3-amidinophenyl)-5-[(2'-trifluoromethyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-trifluoromethyl-4-methoxypyrazole;

1-(3-amidinophenyl)-5-[(2'-trifluoromethyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-trifluoromethyl-pyrazole,

1-(3-amidinophenyl)-5-[(2'-sulfonylmethyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-trifluoromethyl-pyrazole;

1-(3-amidinophenyl)-5-[(2'-aminosulfonyl-3-bromo-[1,1']-biphen-4-yl)aminocarbonyl]-3-methyl-pyrazole;

1-(3-aminocarbonylphenyl)-5-[(2'-aminosulfonyl-3-bromo-[1,1'-biphen-4-yl)aminocarbonyl]-3-methyl-pyrazole;

1-(3-amidinophenyl)-3-methyl-5-[(2'-aminosulfonyl)-[1,1']-biphen-4-yl)methylcarbonyl]pyrazole;

1-(3-aminocarbonylphenyl)-5-[5-[(2'-aminosulfonylphen-1-yl)pyridin-2-yl]aminocarbonyl]-3-methyl-pyrazole;

1-(3-amidinophenyl)-5-[[5-(2'-t-butylaminosulfonylphenyl)pyrimidin-2-yl]aminocarbonyl]-3-trifluoromethyl-pyrazole;

1-(3-amidinophenyl)-5-[[5-(2'-aminosulfonylphenyl)pyrimidin-2-yl]aminocarbonyl]-3-trifluoromethyl-pyrazole;

1-(3-aminocarbonylphenyl)-5-[[5-(2'-aminosulfonylphenyl)pyrimidin-2-yl]aminocarbonyl]-3-trifluoromethyl-pyrazole;

1-(3-cyanophenyl)-5-[((4'-(imidazol-1-yl)phenyl)aminocarbonyl]-3-trifluoromethyl-pyrazole;

1-(3-amidinophenyl)-5-[(4'-(morpholin-1-yl)phenyl)-aminocarbonyl]-3-trifluoromethyl-pyrazole;

1-(3-aminocarbonylphenyl)-5-[(4'-(morpholin-1-yl)phenyl)aminocarbonyl]-3-trifluoromethyl-pyrazole;

1-(3-amidinophenyl)-5-[[5-(2'-aminosulfonylphenyl)pyridin-2-yl]aminocarbonyl]-3-trifluoromethyl-pyrazole;

1-(3-aminocarbonylphenyl)-5-[[5-(2'-aminosulfonylphenyl)pyridin-2-yl]aminocarbonyl]-3-trifluoromethyl-pyrazole;

1-(3-amidinophenyl)-5-[(4'-(3-methyltetrazol-1-yl)phenyl)aminocarbonyl]-3-trifluoromethyl-pyrazole;

1-(3-amidinophenyl)-5-(2'-napthylaminosulfonyl)-3-methyl-pyrazole;

1-(3-amidinophenyl)-5-[(4-bromophenyl)aminosulfonyl]-3-methyl-pyrazole;

1-(3-aminomethylphenyl)-5-[(2'-aminosulfonyl-[1,1]-biphen-4-yl)aminocarbonyl]-3-methyl-pyrazole;

1-(3-aminomethylphenyl)-5-[(2'-aminosulfonyl-[1,1'-biphen-4-yl)aminocarbonyl]-3-trifluoromethyl-pyrazole;

1-(3-amidinophenyl)-3-methyl-5-[((2'-trifluoromethylphenyl)pyrid-2-yl)aminocarbonyl]pyrazole;

1-(3-amidinophenyl)-3-methyl-5-[((2'-aminosulfonyl-1-yl)pyrimid-5-yl)aminocarbonyl]pyrazole;

1-(3-amidinophenyl)-3-methyl-5-[(2'-fluoro-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole;

1-(3-amidinophenyl)-3-methyl-5-[3-chloro-(2'-fluoro-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole;

1-(3-amidinophenyl)-3-methyl-5-[(3-fluoro-2$-fluoro-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole;

1-(3-amidinophenyl)-3-methyl-5-[(3-fluoro-2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole;

1-(3-amidinophenyl)-3-methyl-5-[5-(2'-fluorophen-1-yl)pyrid-2-yl]aminocarbonyl]pyrazole;

1-(3-amidinophenyl)-3-methyl-5-([5-(2'-tertbutylaminosulfonylphenyl)pyrimid-2-yl]aminocarbonyl]pyrazole;

1-(3-amidinophenyl)-3-methyl-5-[[5-(2'-aminosulfonylphenyl)-[1,6]-dihydropyrimid-2-yl]aminocarbonyl]pyrazole;

1-(3-amidinophenyl)-3-methyl-5-[(4-(pyrid-3'-yl)phen-1-yl)aminocarbonyl]pyrazole;

1-(3-amidinophenyl)-3-methyl-5-[[2-(2'-pyridyl)ethyl)aminocarbonyl]pyrazole;

1-(3-amidinophenyl)-3-methyl-5-[(3-phenylpropyl)aminocarbonyl]pyrazole;

1-(3-amidinophenyl)-3-methyl-5-[4-(pyrid-2'-yl)phen-1-ylaminocarbonyl]pyrazole;

1-(3-amidinophenyl)-3-methyl-5-[(4-(isopropyloxy)phenyl)aminocarbonyl]pyrazole;

1-(3-amidinophenyl)-3-methyl-5-[(5-(2'-trifluoromethylphenyl)-pyrimidin-2-yl)aminocarbonyl]pyrazole;

1-(3-amidinophenyl)-3-methyl-5-[(4-(piperidinosulfonyl)phenyl)aminocarbonyl]pyrazole;

1-(3-amidinophenyl)-3-methyl-5-[(4-(piperidinocarbonyl)phenyl)aminocarbonyl]pyrazole;

1-(3-amidino-4-fluorophenyl)-3-methyl-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole;

1-(3-aminocarbonyl-4-fluorophenyl)-3-methyl-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole;

1-methyl-3-(3-amidino)phenyl-4-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole;

1-(3-amidinophenyl)-3-methyl-5-[[4-(pyrazol-41-yl)phen-1-yl]aminocarbonyl]pyrazole;

1-(3-amidinophenyl)-3-methyl-5-([5-(2'-methylsulfonylphenyl)pyrid-2-yl]aminocarbonyl)pyrazole;

1-(3-amidinophenyl)-3-methyl-5-([5-(2'-methylsulfonylphenyl)pyrimid-2-yl]aminocarbonyl)pyrazole;

1-(3-cyanophenyl)-3-methyl-5-([5- (2 -methylsulfonylphenyl)pyrimid-2-yl]aminocarbonyl)pyrazole,;

1-(3-aminocarbonylphenyl)-3-methyl-5-([5- (2'-methylsulfonylphenyl)pyrimid-2-yl]aminocarbonyl)pyrazole;

1-(3-(N-aminoamidino)phenyl)-3-methyl-5-[(2'-tert-butylaminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole;

1-(3-(N-aminoamidino)phenyl)-3-methyl-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole;

1-(3-(N-methyl-N-hydroxyamidino)phenyl)-3-methyl-5-[(4'-t-butylaminosulfonyl-[1,1]-biphen-4-yl)aminocarbonyl]pyrazole;

1-(3-(N-methylamidino)phenyl)-3-methyl-5-[(2'-tert-butylaminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole;

1-(3-(N-methylamidino)phenyl)-3-methyl-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole;

1-(3-amidinophenyl)-5-[(2'-aminosulfonylphenyl)pyridin-2-yl]aminocarbonyl]tetrazole;

1-(3-aminocarbonylphenyl)-5-{[5-(2'-aminosulfonylphenyl)pyridin-2-yl]aminocarbonyl}tetrazole;

1-(3-amidinophenyl)-5-{[5-(2'-trifluoromethylphen-1-yl)pyridin-2-yl]aminocarbonyl}tetrazole;

1-(3-amidinophenyl)-5-[(41-bromophen-1-yl) aminocarbonyl)tetrazole;

1-(3-aminocarbonylphenyl)-5- [5-(2'-trifluoromethylphen-1-yl)pyridin-2-yl]aminocarbonyl}tetrazole;

5-(3-amidinophenyl)-1-[(2'-trifluoromethyl-[1,1']-biphen-4-yl)methyl]tetrazole;

1-[(3-amidinophenyl)methyl]-3-methyl-5-[(2'-aminosulfonyl-[1,1'-biphen-4-yl)aminocarbonyl]pyrazole;

1-[(4-amidinophenyl)methyl]-3-methyl-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole

1-(3-amidinophenyl)-2-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]imidazole;

1-(3-amidinophenyl)-4-methyl-2-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]imidazole;

1-(3-amidinophenyl)-5-chloro-4-methyl-2-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]imidazole;

5-(3-amidinophenyl)-2-methyl-4-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]imidazole;

1-(3-amidinophenyl)-3-methyl-5-[(4'-(benzimidazol-1-yl)phen-1-yl)aminocarbonyl pyrazole;

1-(3-aminocarbonylphenyl)-3-methyl-5-[(4'-(benzimidazol-1-yl)phen-1-yl)aminocarbonyl]pyrazole;

1-(3-amidinophenyl)-3-methyl-5-[(4'-(2-methylimidazol-1-yl)phenyl)aminocarbonyl]pyrazole;

1-(3-aminocarbonylphenyl)-3-methyl-5-[(4'-(2-methylimidazol-1-yl)phenyl)aminocarbonyl)pyrazole;

1-(3-amidinophenyl)-3-methyl-5-[[4'-(1,2,4-triazol-2-yl)-phenyl]aminocarbonyl]pyrazole;

1-(3-amidinophenyl)-3-methyl-5-((4'-cyclohexylphenyl)aminocarbonyl)pyrazole;

1-(3-amidinophenyl)-3-methyl-5-[[1,1']-biphen-4-ylaminocarbonyl]pyrazole;

1-(3-amidinophenyl)-3-methyl-5-((4'-morpholinophenyl)aminocarbonyl)pyrazole;

1-(3-amidinophenyl)-3-methyl-5-[(4'-((2-trifluoromethyl)tetrazol-1-yl)phenyl)aminocarbonyl]pyrazole;

1-(3-aminomethylphenyl)-3-methyl-5-[(4'-((2-trifluoromethyl)tetrazol-1-yl)phenyl)aminocarbonyl]pyrazole;

1-(3-amidinophenyl)-3-methyl-5-[((4'-(N,N-dimethylamino)carbonylamino)phen-1'-yl)aminocarbonyl]pyrazole;

1-(3-amidinophenyl)-3-methyl-5-[(4'-(N,N-diethylamino)phenyl)aminocarbonyl]pyrazole;

1-(3-aminocarbonylphenyl)-3-methyl-5-[((4'-N,N-diethylamino)phenyl)aminocarbonyl]pyrazole;

1-(3-amidinophenyl)-3-methyl-5-[(4'-(1-tetrazolyl)phenyl)aminocarbonyl)pyrazole;

1-(3-aminocarbonylphenyl)-3-methyl-5-((4'-(1-tetrazolyl)phenyl)aminocarbonyl)pyrazole;

1-(3-amidinophenyl)-3-methyl-5-[(4'-(N-acetylpiperizin-1-yl)phenyl)aminocarbonyl]pyrazole;

1-(3-amidinophenyl)-3-methyl-5-[(4'-(N-tert-butyloxycarbonylpiperizin-1-yl)phenyl)aminocarbonyl]pyrazole,;

1-(3-amidinophenyl)-3-methyl-5-((41-piperizin-1-yl-phenyl)aminocarbonyl)pyrazole;

1-(3-amidinophenyl)-3-trifluoromethyl-5-((4'-cyclohexylphenyl)aminocarbonyl)pyrazole;

1-(3-amidinophenyl)-3-methyl-5-[(4'-(N-morpholino)-3'-chlorophenyl)aminocarbonyl]pyrazole;

1-(3-amidinophenyl)-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-(methylthio)pyrazole;

1-(3-amidinophenyl)-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-(methylsulfinyl)pyrazole;

1-(3-amidinophenyl)-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-(methylsulfonyl)pyrazole;

1-(3-aminocarbonylphenyl)-5-[(2'-trifluoromethyl-[1,1]-biphen-4-yl)methyl]tetrazole;

1-(3-aminocarbonylphenyl)-5-{[(2'-aminosulfonyl-[1,1']-biphen-4-yl)methyl}tetrazole;

1-(3-amidinophenyl)-5-[(4'-cyclopentyloxyhenyl)aminocarbonyl]-3-methyl-pyrazole;

1-(3-amidinophenyl)-5-[(3-((pyrid-2-yl)methylamino)phenyl) aminocarbonyl]-3-methyl-pyrazole;

1-(3-amidinophenyl)-3-methyl-5-[(4'-(N-imidazolyl)phenyl)aminocarbonyl3pyrazole;

1-(3-amidinophenyl)-3-trifluoromethyl-5-[(4'-(N-morpholino)-3-chlorophenyl)aminocarbonyl]pyrazole;

1-(3-amidinophenyl)-3-methyl-5-[(4'-(N-pyrrolidinocarbonyl)-3'-chlorophenyl)aminocarbonyl]pyrazole;

1-(3-amidinophenyl)-3-methyl-5-[(4'-(N-morpholinocarbonyl)-3-chlorophenyl)aminocarbonyl]pyrazole;

1-(3-cyanophenyl)-5-[(4'-(N-imidazolyl)phenyl)aminocarbonyl]-3-trifluoromethyl-pyrazole;

1-(3-amidinophenyl)-5-[(4'-(N-imidazolyl)phenyl)aminocarbonyl]-3-trifluoromethyl-pyrazole;

1-(3-amidinophenyl)-5-[(4'-(N-methyltetrazolon-1-yl)phenyl)aminocarbonyl]-3-trifluoromethyl-pyrazole;

1-(3'-aminocarbonylphenyl)-5-[(2'-aminosulfonylphenyl-[1,1']-biphen-4-yl)methylcarbonyl]-3-methyl-pyrazole;

1-(3-amidinophenyl)-5-[4'-(pyrrolidinomethyl)phenyl) aminocarbonyl]-3-methyl-pyrazole;

1-(3-aminophenyl)-3-methyl-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole;

1-(2'-aminophenyl)-3-methyl-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole;

1-(3-amino-4'-chlorophenyl)-3-methyl-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole;

1-(3-amino-4'-fluorophenyl)-3-methyl-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole;

1-(3-amino-4'-methoxyphenyl)-3-methyl-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole;

1-(3-amino-4'-chlorophenyl)-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl)tetrazole;

1-(3-amino-4'-chlorophenyl)-5-{[(2'-aminosulfonylphenyl)pyridin-2-yl]aminocarbonyl}tetrazole;

1-(3-amino-4'-methoxyphenyl)-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]tetrazole;

1-(3-aminomethylphenyl)-5-[(2'-aminosulfonylphenyl)pyrid-2-yl) aminocarbonyl]-3-methyl-pyrazole;

1-(3-aminomethyl-4'-methylphenyl)-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-methyl-pyrazole;

1-(3-aminomethyl-4'-fluorophenyl)-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-methyl-pyrazole;

1-(3-aminomethylphenyl)-5-[(4'-(N-pyrrolidino-carbonyl)phenyl)aminocarbonyl]-3-trifluoromethyl-pyrazole;

1-(3-Ethylcarboxyamidinophenyl)-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)-aminocarbonyl]-3-methyl-pyrazole;

1-(3-(1'-imino-1'-(N-morpholino))methyl)phenyl)-5-[(2'-tert-butylaminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-methyl-pyrazole;

1-(3-(1'-imino-1'-(N-morpholino))methyl)phenyl)-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-methyl-pyrazole;

1-[3-[N-((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxycarbonyl)amidinolphenyl]-5-((2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl)-3-methyl-pyrazole;

1-(pyrid-2-yl)-3-methyl-5-[(3-fluoro-2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole;

1-(6-bromopyridin-2-yl)-3-methyl-5-[(3-fluoro-2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole;

1-(3-amino-4-chlorophenyl)-5-[(2'-aminosulfonyl-3-chloro-[1,1']-biphen-4-yl)aminocarbonyl]tetrazole;

1-(3-amino-4-chlorophenyl)-5-[(41-(1-pyrrolidinocarbonyl)phenyl)aminocarbonyl]tetrazole;

1-(3-aminomethylphenyl)-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]tetrazole;

1-(3-aminomethylphenyl)-5-[(2'-aminosulfonyl-3-fluoro-[1,1']-biphen-4-yl)aminocarbonyl]tetrazole;

1-(3-aminomethylphenyl)-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]imidazole;

1-(3-aminomethylphenyl)-5-[(2'-methylsulfonylmethyl-[1,1']-biphen-4-yl)aminocarbonyl]imidazole;

1-(3-amidinophenyl)-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]imidazole;

1-[3-(methylaminomethyl)phenyl]-5-[(2'-aminosulfonyl-3-fluoro-[1,1']-biphen-4-yl)aminocarbonyl]-3-methyl-pyrazole;

1-[3-(methylaminomethyl)phenyl]-5-[(2'-methylsulfonyl-3-fluoro-[1,1']-biphen-4-yl)aminocarbonyl]-3-methyl-pyrazole;

1-(3-aminomethylphenyl)-5-[(2'-methylsulfonyl-[1,1I]-biphen-4-yl)aminocarbonyl]-4-methoxy-3-trifluoromethyl-pyrazole;

1-(3-aminomethylphenyl)-5-[(2-fluoro-4-(N-pyrrolidinocarbonyl)phenyl)aminocarbonyl]-3-trifluoromethyl-pyrazole;

1-(3-aminomethylphenyl)-5-[(3-fluoro-4-(N-pyrrolidinocarbonyl) phenyl)aminocarbonyl]-3-trifluoromethyl-pyrazole;

1-(3-aminomethylphenyl)-5- [(2'-sulfonylmethyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-trifluoromethyl-pyrazole;

1-(3-aminomethylphenyl)-5-[(2'-aminosulfonyl-3-fluoro-[1,1'] biphen-4-yl)aminocarbonyl]-3-trifluoromethyl-pyrazole;

1-(3-aminomethylphenyl)-5-[(5-(2'-aminosulfonylphenyl)-[1,6-dihydro]pyrimid-2-yl)aminocarbonyl]-3-trifluoromethyl-pyrazole;

1-(3-aminomethylphenyl)-5-[(5-(2'-aminosulfonylphenyl)pyrimid-2-yl)aminocarbonyl]-3-trifluoromethyl-pyrazole;

1-[3-(2'-ethylaminophenyl)-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-trifluoromethyl-pyrazole;

1-[3-(1-(N-morpholino)imino)phenyl]-5-((2'-aminosulfonyl-3-fluoro-[1,1']-biphen-4-yl)aminocarbonyl]-3-trifluoromethyl-pyrazole;

1-(3-aminomethylphenyl)-5-[2-(2'-aminosulfonyl-[1,1']-biphen-4-yl)-1-hydroxyethyl]-3-trifluoromethyl-pyrazole;

1-(3-aminomethylphenyl)-5-[(3-fluoro-2'-methylsulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-trifluoromethyl-pyrazole;

1-(3-aminomethylphenyl)-5-[(5-(2'-methylsulfonyl-phenyl)pyrimid-2-yl)aminocarbonyl]-3-trifluoromethyl-pyrazole;

1-[3-amidinophenyl]-5-[(3-fluoro-2'-methylsulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-trifluoromethyl-pyrazole;

1-[3-amidinophenyl]-5-[(3-fluoro-2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl1-3-trifluoromethyl-pyrazole;

1-(3-aminomethyl)phenyl-5-[(2'-aminosulfonyl-[1,1 1-biphen-4-yl)carbonylmethyl]-3-trifluoromethyl-pyrazole;

1-(3-aminomethyl)phenyl-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-(methylsulfonylmethyl)pyrazole;

1-(3-amidino)phenyl-5-[(2'-aminosulfonyl-[1,1l1-biphen-4-yl)aminocarbonyl)-3-(methylaminosulfonylmethyl)pyrazole;

1-(3-aminomethylphenyl)-5-[(2'-aminosulfonyl-3-fluoro-[1,1']-biphen-4-yl)aminocarbonyl)-3-(methylaminosulfonylmethyl)pyrazole;

1-(3-(N-carboxymethyl)amidinophenyl)-5-[(5-(2'-aminosulfonylphenyl)pyrimid-2-yl)aminocarbonyl]-3-methyl-pyrazole;

1-(3-aminomethylphenyl)-5-[(2'-methylsulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-methyl-pyrazole;

1-(3-aminomethylphenyl)-5-[(2'-aminosulfonyl-3-methyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-trifluoromethyl-pyrazole;

1-(3-aminomethylphenyl)-5-[(3-fluoro-2'-methylsulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-1,2,3-triazole;

1-(3-aminomethyl-4-methyl)phenyl-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-methyl-pyrazole;

1-(3-aminomethyl-4-fluoro)phenyl-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-methyl-pyrazole;

1-(3-aminomethyl-4-chloro)phenyl-5-((2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-methyl-pyrazole;

1-(3-aminomethyl-4-fluoro)phenyl-5-[(2'-aminosulfonyl-3-fluoro-[1,1']-biphen-4-yl)aminocarbonyl]-3-trifluoromethyl-pyrazole;

5 1-(3-aminomethyl)phenyl-5-[(2'-aminosulfonyl-3-fluoro-[1,1']-biphen-4-yl)aminocarbonyl]-3-methyl-pyrazole;

1-(3-aminomethyl)phenyl-5-[(3-fluoro-2'-methylsulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-trifluoromethyl-pyrazole;

1-(3-amidinophenyl)-3-methyl-5-[(3-fluoro-4-(N-morpholino)phenyl)aminocarbonyl]pyrazole;

1-(3-aminomethylphenyl)-3-methyl-5-[(3-fluoro-4-(N-morpholino)phenyl)aminocarbonyl]pyrazole;

1-(3-aminomethylphenyl)-3-trifluoromethyl-5-((3-fluoro-4-(2-methylimidazol-l-yl)phenyl)aminocarbonyl)pyrazole;

1-(3-cyanophenyl)-3-trifluoromethyl-5-(([1,1']-biphen-4-yl)oxymethyl)pyrazole;

1-(3-amidinophenyl)-3-trifluoromethyl-5-[([1,1']-biphen-4-yl)oxymethylipyrazole;

1-(3-carboxamidophenyl)-3-trifluoromethyl-5-(([1,1']-biphen-4-yl)oxymethyl)pyrazole;

1-(3-amidinophenyl)-3-trifluoromethyl-5-((2-fluoro-4-(N-morpholino)phenyl)aminocarbonyl)pyrazole;

1-(3-carboxamidophenyl)-3-trifluoromethyl-5-((2-fluoro-4-(N-morpholino)phenyl)aminocarbonyl)pyrazole;

1-(3-aminomethylphenyl)-3-trifluoromethyl-5-((3-trifluoromethyl-4-(N-morpholino)phenyl)aminocarbonyl)pyrazole;

1-(3-aminomethylphenyl)-3-ethyl-5-[(3-fluoro-2'-tert-butylaminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole;

1-(3-aminomethylphenyl)-3-ethyl-5-((3-fluoro-2'-methylsulfonyl-[1,1']-biphen-4-yl))aminocarbonyl)pyrazole;

1-(3-aminomethylphenyl)-3-ethyl-5-[(2-fluoro-4-(2-methylsulfonylimidazol-1-yl)phenyl)]aminocarbonyl)pyrazole;

1-[(6-(aminomethyl)pyrid-2-yl)]-3-methyl-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole;

1-[(6-(N-hydroxyamidino)pyrid-2-yl)]-3-methyl-5-[(2'-tert-butylaminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole;

1-[(6-amidinopyrid-2-yl)]-3-methyl-5-[(2'-aminosulfonyl-[1,1]-biphen-4-yl)aminocarbonyl]pyrazole;

1-[6-amidinopyrid-2-yl]-3-methyl-5-[³ -fluoro-(2'-methylsulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole;

1-(3-aminomethylphenyl)-3-methyl-5-((2-methoxy-4-(N-morpholino)phenyl) aminocarbonyl)pyrazole;

1-(3-aminomethylphenyl)-3-methyl-5-[4'-(3"-methyl-5"-oxo-3"-pyrazolin-2"-yl)-phenyl)aminocarbonyl]pyrazole;

1-[3-(aminomethyl)phenyl]-5-[(2'-methylsulfonyl-[1,1 ]-biphen-4-yl)aminocarbonyl]-3-(methylthio)pyrazole;

1-(3-aminomethyl-4-fluorophenyl)-3-trifluoromethyl-5-[(3-fluoro-2'-methylsulfonyl-[1,1l]-biphen-4-yl)aminocarbonyl]pyrazole;

ethyl 1-[3-(aminomethyl)-phenyl]-5-[3-fluoro-2'-methylsulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole-3-carboxylate;

1-[3-(aminomethyl)phenyl]-5-[(3-fluoro-2'-methylsulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole-3-carboxylic acid;

1-[3-(aminomethyl)phenyl]-3-[aminocarbonyl]-5-[³ -fluoro-(2'-methylsulfonyl-[1,1]-biphen-4-yl)aminocarbonyl]pyrazole;

ethyl 1-[3-(aminomethyl)-phenyl]-3-trifluoromethyl-5-[(3-fluoro-2¹ -methylsulfonyl- [1,1']-biphen-4-yl)aminocarbonylpyrazole-4-carboxylate;

1-[3-(aminomethyl)phenyl]-5-[(3-fluoro-2,'-methylsulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-(methylthio)pyrazole;

1-[3-(aminomethyl)phenyl]-5-[(³ -fluoro-2'-methylsulfonyl-[1,1'--biphen-4-yl)aminocarbonyl]-3-(methylsulfonyl)pyrazole;

1-[3-(aminomethyl)phenyl]-5-[(4-(5-(methoxyaminocarbonyl)imidazol-1-yl)phen-1-yl)aminocarbonyl.1-3-trifluoromethyl-pyrazole; and,

1-(³ -aminomethylphenyl)-5-[(4-(5-methyl-1,2,3-triazol-1-yl)phen-1-yl)aminocarbonyl]-3-trifluoromethyl-pyrazole;

and pharmaceutically acceptable salts thereof.

In a second embodiment, the present invention provides novel pharmaceutical compositions, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt form thereof.

In a third embodiment, the present invention provides a novel method for treating or preventing a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt form thereof.

DEFINITIONS

The compounds herein described may have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. Many geometric isomers of olefins, C═N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated.

The term "substituted," as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. When a substitent is keto (i.e., ═O), then 2 hydrogens on the atom are replaced.

When any variable (e.g., R⁶) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R⁶, then said group may optionally be substituted with up to two R⁶ groups and R⁶ at each occurrence is selected independently from the definition of R⁶. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

As used herein, "C₁₋₆ alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, examples of which include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, pentyl, and hexyl; "Alkenyl" is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl, propenyl, and the like.

"Halo" or "halogen" as used herein refers to fluoro, chloro, bromo, and iodo; and "counterion" is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate, and the like.

As used herein, "carbocycle" or "carbocyclic residue" is intended to mean any stable 3- to 7-membered monocyclic or bicyclic or 7- to 13-membered bicyclic or tricyclic, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl,; [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin).

As used herein, the term "heterocycle" or "heterocyclic system" is intended to mean a stable 5- to 7- membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic ring which is saturated partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. If specifically noted, a nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1. As used herein, the term "aromatic heterocyclic system" is intended to mean a stable 5- to 7-membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic aromatic ring which consists of carbon atoms and from 1 to 4 heterotams independently selected from the group consisting of N, O and S. It is preferred that the total number of S and O atoms in the aromatic heterocycle is not more than 1.

Examples of heterocycles include, but are not limited to, 1H-indazole, 2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, carbazolyl, 4aH-carbazolyl, β-carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl., oxazolyl, oxazolidinylperimidinyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, guinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, xanthenyl. Preferred heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, or isatinoyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.

The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.

"Prodrugs" are intended to include any covalently bonded carriers which release the active parent drug according to formula (I) in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of formula (I) are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of formula (I) wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug or compound of formula (I) is administered to a mammalian subject, cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of formula (I), and the like. Preferred prodrugs are amidine prodrugs wherein D is C(═NR⁷)NH₂ or its tautomer C(═NH)NHR⁷ and R⁷ is selected from OH, C₁₋₄ alkoxy, C₆₋₁₀ aryloxy, C₁₋₄ alkoxycarbonyl, C₆₋₁₀ aryloxycarbonyl, C₆₋₁₀ arylmethylcarbonyl, C₁₋₄ alkylcarbonyloxy C₁₋₄ alkoxycarbonyl, and C₆₋₁₀ arylcarbonyloxy C₁₋₄ alkoxycarbonyl. More preferred prodrugs are where R⁷ is OH, methoxy, ethoxy, benzyloxycarbonyl, methoxycarbonyl, and methylcarbonyloxymethoxycarbonyl.

"Stable compound" and "stable structure" are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

SYNTHESIS

The compounds of the present invention can be prepared in a number of ways known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or by variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. The reactions are performed in a solvent appropriate to the reagents and materials employed and suitable for the transformations being effected. It will be understood by those skilled in the art of organic synthesis that the functionality present on the molecule should be consistent with the transformations proposed. This will sometimes require a judgment to modify the order of the synthetic steps or to select one particular process scheme over another in order to obtain a desired compound of the invention. It will also be recognized that another major consideration in the planning of any synthetic route in this field is the judicious choice of the protecting group used for protection of the reactive functional groups present in the compounds described in this invention. An authoritative account describing the many alternatives to the trained practitioner is Greene and Wuts (Protective Groups In Organic Synthesis, Wiley and Sons, 1991). All references cited herein are hereby incorporated in their entirety herein by reference.

The compounds of Formula I in which ring M is pyrrole can be prepared by the procedures described in Schemes 1-9. In Scheme 1 is shown how to prepare pyrroles in which the group Q--E is attached to the pyrrole nitrogen, wherein Q is a functionality that can be converted into D of Formula I, R^(e) is functionality that can be converted into Z--A--B of Formula I and R^(f) is or can be converted into R^(1a) of Formula I. Oxidation of a furan with bromine in acetic acid can afford a 2,5-diacetoxydihydrofuran which can react with amine Q--E--NH2 to afford a pyrrole. Vilsmeier-Haack formylation with phosphorous oxychloride and DMF preferentially can acylate the pyrrole ring at C-2. Oxidation of the resulting aldehyde can give a carboxylic acid. The carboxylic acid can then be converted into amine derivatives using either the Hofmann degradation of the derived primary amide (Huisgen et. al. Chem. Ber. 1960, 93, 65) or the Curtius rearrangement of the derived acyl azide (J. Prakt. Chem. 1909, 42, 477). Derivatives which contain a sulfur atom attached to the pyrrole ring can be obtained by direct sulfonation with pyridine sulfur trioxide complex to give the sulfonic acids or treatment with copper (II) thiocyanate (J. Het. Chem. 1988, 25, 431) followed by the reduction of the intermediate thiocyanate with sodium borohydride to give a mercaptan. ##STR11##

In Scheme 2 is shown how to prepare pyrroles in which Q--E is attached to the 2-position, wherein R^(f) and R^(g) collectively are hydrogen or a group that can be converted into R^(1a) and R^(1b) of Formula I. The Hantzsch pyrrole synthesis is a versatile reaction involving the cyclization of an appropriate β-ketoester with an α-halo ketone or aldehyde in the presence of a primary amine (Ber. Dtsch. Chem. Ges. 1890, 23, 1474). The β-ketoesters can be prepared from acid chlorides (X═Cl) by the addition of the magnesium anion of potassium alkylmalonate followed by decarboxylation (Synthesis 1993, 290). Alternatively, β-ketoesters can be prepared from an appropriate aldehyde (R═H) by Reformatsky reaction with an α-bromoacetate followed by oxidation. Cyclization with an α-halo ketone or aldehyde in the presence of a primary amine can afford pyrroles. Acidic hydrolysis of the 3-carboalkoxy pyrrole can afford the carboxylic acids. Pyrroles which contain a 3-amino substituent can be prepared from the acids by treatment with phosphoryl azide and triethylamine to effect a Curtius rearrangement to afford the isocyanates (J. Med. Chem. 1981, 24, 33) which upon hydrolysis can yield 3-aminopyrroles. Pyrroles which contain a sulfur atom at C-3 can be prepared from the acids by employing the Hunsdiecker procedure to give the 3-bromo derivatives. Halogen-metal exchange at low temperature with an alkyllithium reagent can afford the 3-lithio derivative which can be quenched with a variety of electrophiles, such as S₈ to afford thiols directly or Cu(SCN)₂ to afford a thiocyanate which can be reduced with sodium borohydride. The thiols can further be oxidized to the sulfonic acid derivatives by an oxidant such as KMnO₄. ##STR12##

In Scheme 3 is shown how to prepare pyrroles in which Q--E is attached to the 3-position. This scheme relies upon the extremely versatile Knorr pyrrole synthesis, which involves condensation of α-aminoketones with β-ketoesters. The α-aminoketones can be prepared from β-ketoesters (Scheme 2) by nitrosation followed by reduction with zinc/acetic acid. Condensation of α-aminoketones with appropriate β-ketoesters can afford good yields of pyrroles. These intermediates are very versatile and can be converted into pyrroles with a wide variety of substituents with varying substitution patterns. For cases wherein R^(e) (Z--A--B precursor) is at the 2-position, acidic hydrolysis can selectively hydrolyze the C-3 ester. Heating should then effect decarboxylation. Hydrolysis of the 2-carboxylic acid can be achieved under basic conditions. Curtius rearrangement of the acid as described previously can afford the amino derivatives. To prepare compounds with a sulfur atom attached to C-2, basic hydrolysis and decarboxylation can afford the C-2 unsubstituted pyrroles. These pyrroles can undergo electrophilic substitution to afford thiols (Cu(SCN)₂, then NaBH₄) and sulfonic acids (pyridine SO₃ complex or chlorosulfonic acid). The R^(1a) group contained in Formula I can be derived either from the remaining ester or from R^(f). Alternatively, the thiol and sulfonic acid derivatives can also be derived form the C-2 acids by manipulation of the carboxylic acid group as described previously. ##STR13##

In Scheme 4 is shown how to prepare pyrroles in which Q--E is attached to the 3-position Cyclization of α-aminoketones as described previously with β-ketoesters can afford pyrroles. Hydrolysis under basic conditions can selectively hydrolyze the C-2 ester which upon heating should undergo decarboxylation to afford 2-unsubstituted pyrroles The C-3 ester can then be hydrolyzed under acidic conditions to afford the 3-carboxypyrroles Curtius rearrangement under conditions described previously can afford the 3-aminopyrroles. The carboxylic acids can be used to prepare the 3-mercapto and 3-sulfonic acid derivatives- The Hunsdiecker procedure can be used to prepare the 3-bromopyrroles. Halogen metal exchange with t-BuLi at low temperature followed by quenching with copper isocyanate should introduce an isocyanate group at C-3. This intermediate can be reduced with sodium borohydride to afford the 3-mercaptopyrroles. Alternatively, the carboxylic acids can be decarboxylated to afford pyrroles which can be N-protected with a bulky protecting group such as triisopropylsilyl (TIPS). This bulky group directs electrophilic substitution to C-3 of the pyrrole ring. Thus, reaction with copper isocyanate followed by sodium borohydride reduction and then fluoride induced TIPS deprotection can afford 3-mercaptopyrroles. Sulfonation of N-protected pyrrole with pyridine sulfur trioxide complex can again be directed to C-3 of the pyrrole to afford, after TIPS deprotection, the 3-sulfonic acids. ##STR14##

Another general method of pyrrole synthesis that can be used to prepare compounds of the present invention is shown in Scheme 5. This approach (Cushman et. al J. Org. Chem. 1996, 61, 4999) uses N-protected α-aminoketones and N-protected α-aminoaldehydes which are readily available from α-amino acids by initial preparation of the N-methoxy-N-methylamides followed by addition of an alkyl Grignard reagent (to produce ketones) or by reduction with a hydride reducing agent such as lithium aluminum hydride or diisobutylaluminum hydride. These aldehydes and ketones can be allowed to react with the enolates of additional ketones to afford intermediate aldol addition products which under acidic conditions cyclize to form pyrroles. The reacting partners in this approach can be of wide scope and can be chosen so that one skilled in the art will be able to prepare varied pyrroles. ##STR15##

Another very general method of pyrrole synthesis useful for preparing compounds of the present invention is the Paal-Knorr reaction shown in Scheme 6. This reaction involves the reacting 1,4-diketones or 1,4-ketoaldehydes with primary amines to afford pyrroles. The starting 1,4-diketones and 1,4-ketoaldehydes can be prepared using standard enolate chemistry or by other procedures which are familiar to those skilled in the art of organic synthesis. The reaction is of wide scope and the starting materials can be chosen so that a variety of pyrroles can be prepared. ##STR16##

In Scheme 7 is shown how the compounds of Schemes 1-6 wherein R^(e) is a carboxylic ester group can be converted into compounds containing the Z--A--B residue. For the amide linker (Formula I, Z═--CONH--), when R^(e) ═carboalkoxy, it can be hydrolyzed to the acid under either basic or acidic conditions depending on the substitution pattern, as described previously. Formation of the acid chloride with thionyl chloride followed by the addition of an appropriate amine H₂ N--A--B can afford the amide-linked compounds. Alternatively, the acid can be combined with amine H₂ N--A--B in the presence of a suitable peptide coupling agent, such as BOP--Cl, HBTU or DCC. In another method the ester can be directly coupled with an aluminum reagent, prepared by the addition of trimethylaluminum to the amine H₂ N--A--B.

To form ether- or thioether-linked compounds of Formula I (Z═--CH₂ O--, --CH₂ S--) the acid can be reduced to the alcohol. Preferred procedures for this transformation are reduction with borane THF complex, or a procedure involving the reduction of the mixed anhydride with sodium borohydride (IBCF═isobutyl chloroformate and NMM═N-methylmorpholine). Completion of the ether and thioether linked compounds of Formula I can readily be accomplished by the Mitsonobu protocol with an appropriate phenol, thiophenol or hydroxy- or mercaptoheterocycle HX--A--B (X═O,S) (Formula I, A=aryl or heteroaryl). Other ethers or thioethers (X═O,S) can be prepared following initial conversion of the alcohol to a suitable leaving group, such as tosylate. Where X═S, thioethers can be further oxidized to prepare the sulfones (Formula I, Z═--CH₂ SO₂ --).

To prepare the amine-linked compounds of Formula I (Z═--CH₂ NH--) the alcohol can be oxidized to the aldehyde by a number of procedures, two preferred methods of which are the Swern oxidation and oxidation with pyridinium chlorochromate (PCC). Alternatively, the aldehyde may be directly prepared by direct formylation of the pyrrole ring by the Vilsmeier-Haack procedure in certain cases, as described in previous schemes- Reductive amination of the aldehyde with an appropriate amine H₂ N--A--B and sodium cyanoborohydride can then afford the amine linked compounds.

The aldehyde also can be used to prepare the ketone-linked compounds of Formula I (Z═--COCH₂ --). Treatment with an organometallic species can afford the alcohol. The organometallic species (wherein M=magnesium or zinc) can preferably be prepared from the corresponding halide by treatment with metallic magnesium or zinc. These reagents should readily react with aldehydes to afford alcohols. Oxidation of the alcohol by any of a number of procedures, such as the Swern oxidation or PCC oxidation, can afford the ketones-linked compounds. ##STR17##

Additional compounds of Formula I in which the linking group m/z contains a nitrogen atom attached to ring M can be prepared by the procedures described in Scheme 8. The amines can be converted to sulfonamides (Formula I, m/z--NHSO₂ --) by treatment with an appropriate sulfonyl chloride B--A--SO₂ Cl in the presence of a base such as triethylamine. The amines can be converted into amides (Formula I, Z═--NHCO--) by treatment with an appropriate acid chloride Cl--CO--A--B in the presence of a base or by treatment with an appropriate carboxylic acid HO--CO--A--B in the presence of a suitable peptide coupling agent, such as DCC, HBTU or BOP. The amines can also be converted into amine-linked compounds (Formula I, Z═--NHCH₂ --) by reductive amination with an appropriate aldehyde OHC--A--B. ##STR18##

Additional compounds of Formula I in which the linking group Z contains a sulfur atom attached to ring M can be prepared by the procedures described in Scheme 9. Treatment of sulfonic acids with phosphorous pentachloride followed by treatment with an appropriate amine H₂ N--A--B can afford sulfonamide-linked compounds (Formula I, Z═--SO₂ NH--). The thiols can be alkylated with a suitable alkylating reagent in the presence of a base to afford thioethers (Formula I, Z═--SCH₂ --). These compounds can be further oxidized by a variety of reagents to afford the sulfone-linked compounds (Formula I, Z═--SO₂ CH₂ --). ##STR19##

Compounds of Formula I wherein ring M is an imidazole can be formed using procedures described in Schemes 10-16. N-Substituted imidazole derivatives can be made by the general procedure shown in Scheme 10, wherein V' is either V or a precusor of (CH₂)_(n) V, V is nitro, amino, thio, hydroxy, sulfonic acid, sulfonic ester, sulfonyl chloride, ester, acid, or halide, n is 0 and 1, and PG is either a hydrogen or a protecting group. Substitution can be achieved by coupling an imidazole with a halogen containing fragment Q--E--G--Hal in the presence of a catalyst, such as base, Cu/CuBr/base, or Pd/base, followed by conversion of V' to (CH₂)_(n) V. Then, Q can be converted to D, and finally V can be converted to --Z--A--B following the procedures outlined in Schemes 7-9. Alternatively, V can be converted to Z--A--B followed by deprotection of N. This product can then be coupled as before to obtain the desired imidazole. ##STR20##

One way to make amidino-phenyl-imidazole derivatives is shown in Scheme 11. Imidazole carboxylic acid can be treated with thionyl chloride and then coupled with H₂ N--A--B in the presence of a base and then be heated with 3-fluorobenzonitrile in the presence of a base. The Pinner reaction using standard procedures known to those of skill in the art can be used to form the amidino group. ##STR21##

1,2-Disubstituted and 1,5-disubstituted imidazole derivatives can be made by the general procedures described in Scheme 12, wherein R^(1b) is either a hydrogen or an alkyl group and U is aldehyde, ester, acid, amide, amino, thiol, hydroxy, sulfonic acid, sulfonic ester, sulfonyl chloride, or methylene halide. Step a involves coupling in the presence of a catalyst, such as base, Cu/CuBr/base, or Pd/base. When R^(1b) is a hydrogen, it can be deprotonated with a lithium base and trapped by forinate, formamide, carbon dioxide, sulfonyl chloride (sulfur dioxide and then chlorine), or isocyanate to give 1,2-disubstituted imidazoles (Route b1). Also, in Route b1 when R^(1b) is CH₃, it can be oxidized with SeO₂, MnO₂, NaIO₄ /cat. RhCl₃, or NBS to form U. When R^(1b) is hydrogen, sequential deprotonation and quenching with a lithium base and trimethysilyl chloride, followed by a second deprotonation with a lithium base and quenching with formate, formamide, carbon dioxide, sulfonyl chloride (sulfur dioxide and then chlorine), or isocyanate can afford 1,5-disubstituted imidazoles (Route b2). When R^(1b) is not hydrogen, the procedure of Route b2 can again be used to form 1,5-disubstituted imidazoles (Route b3). ##STR22##

A preferred way of making 1,2-disubstituted and 1,5-disubstituted imidazole derivatives is shown in Scheme 13. Imidazole can be heated with 3-fluorobenzonitrile in the presence of a base. The coupled product can then be treated with an alkyl lithium base and quenched with ClCO₂ Me to give the 1,2-disubstituted compound. Further treatment with a solution prepared of H₂ N--A--B in trimethylaluminum can give the amide, which can be further modified via the Pinner reaction to form the desired compound. The 1,5-disubstituted compounds can be made using the same procedure, except that the initial anion is protected and a second anion is formed which is then quenched as noted above. Further modifications can follow the same procedures as the 1,2-disubstituted compounds. ##STR23##

Another way of making 1,2-disubstituted imidazole derivatives is described in Scheme 14. By reacting an N-substituted imidazole with a cyanate, the amide can be obtained. This amide can then be coupled with group B as will be described later. ##STR24##

Another means of making 1,5-disubstituted imidazole derivatives is described in Scheme 15. Alkylation with 2-bromoethylacetate and subsequent reaction with Gold's reagent in the presence of a base, such as NaOMe, or LDA, can form ester substituted imidazoles which can be further modified as previously discribed. ##STR25##

A general procedure to make 2,4,5-trisubstituted or 4,5-disubstituted imidazole derivatives is shown in Scheme 16. After metal halogen exchange of the Q--E--G fragment, it can be reacted with the amide shown, brominated with NBS and cyclized with excess NH₃ and R^(1a) CO₂ H to afford an imidazole. This can then be modified as before. ##STR26##

A general procedure to make 4,5-disubstituted triazole derivatives is described in Scheme 17. Ethyl propiolate can be substituted in the presence of CuI/Pd and then reacted with NaN₃ to form a triazole. The triazole can be converted as described previously. ##STR27##

The tetrazole compounds of the present invention where Z is --CONH-- can be prepared as exemplified in Scheme 18. An appropiately substituted amine can be acylated with ethyl oxalyl chloride. The resulting amide can be converted to the tetrazole either by the methods described by Duncia (J. Org. Chem. 1991, 2395-2400) or Thomas (Synthesis 1993, 767-768). The amide can be converted to the iminoyl chloride first and the reacted with NaN₃ to form the 5-carboethoxytetrazole (J. Org. Chem. 1993, 58, 32-35 and Bioorg. & Med. Chem. Lett. 1996, 6, 1015-1020). The 5-carboethoxytetrazole can then be further modified as described in Scheme 7.

The tetrazole compounds of the present invention where Z is --CO-- can also be prepared via iminoyl chloride (Chem. Ber. 1961, 94, 1116 and J. Org. Chem. 1976, 41, 1073) using an appropriately substituted acyl chloride as starting material. The ketone-linker can be reduced to compounds wherein Z is alkyl. ##STR28##

The methods described in Scheme 18 can also be used to synthesize compounds where the E--Q is linked to the carbon atom of the tetrazole as shown in Scheme 19. The 5-substituted tetrazole can then be alkylated or acylated to give the desired products. ##STR29##

The tetrazole compounds of the present invention wherein Z is --SO₂ NH--, --S--, --S(O)--, SO₂ can be prepared from the thiol prepared as shown in Scheme 20. Appropiately substituted thioisocyanate can be reacted with sodium azide to give the 5-thiotetrazole (J. Org. Chem. 1967, 32, 3580-3592). The thio-compound can be modified as described in Scheme 9.

The tetrazole compounds of the present invention wherein Z is --O-- can be prepared via the same method described in Scheme 20 by using appropiately substituted isocyanate as the starting material. The hydroxy compound can be modified similarily to the thiols described in Scheme 9. ##STR30##

The tetrazole compounds of the present invention wherein Z is --NH--, --NHCO--, --NHSO₂ -- can be prepared from 5-aminotetrazole, which can be prepared by Smiles Rearrangement as shown in Scheme 21. The thio-compound prepared as described in Scheme 20 can be alkylated with 2-chloroacetamide. The resulting compound can then be refluxed in ethanolic sodium hydroxide to give the corresponding 5-amino-tetrazole (Chem. Pharm. Bull. 1991, 39, 3331-3334). The resulting 5-amino-tetrazole can then be alkylated or acylated to form the desired products. ##STR31##

Pyrazoles of Formula I (such as those described in Scheme 22) can be prepared by the condensation of an appropriately substituted hydrazine with a variety of diketo esters. Condensations of this type typically afford a mixture of pyrazole regioisomers which can be effectively separated via silica gel column chromatography. The esters can be converted to Z--A--B as previously described.

Alternatively, if in Scheme 22, the starting diketone contains CH₃ in place of CO₂ Et, then the resulting methyl pyrazole can be separated and oxidized as in Route b1 in Scheme 12 to form the pyrazole carboxylic acid. ##STR32##

When ketoimidates are used for condensations with hydrazines the corresponding pyrazole amino esters are obtained (Scheme 23). Conversion of these intermediates to the final compounds of formula I can then be accomplished by the protection of the amino functionality with a suitable protecting group or by derivatization (e.g. sulfonamide) and then modifying the ester as previously noted. ##STR33##

As shown in Scheme 24, pyrazoles wherein the 4-position is substituted can be prepared by bromination (bromine or NBS in either dichloromethane or acetic acid) of the initial pyrazole. Conversion of 4-bromo-pyrazole to 4-carboxylic acid pyrazole can be accomplished by a number of methods commonly known to those in the art of organic synthesis. Further manipulations as previously described can afford pyrazoles of the present invention. ##STR34##

Pyrazoles can also be prepared according to method described in Scheme 25. The bromo-pyrazoles are formed as in Scheme 24. QE can then be coupled using palladium catalysed Suzuki cross-coupling methodology. Further modification is achieved as previously described. ##STR35##

5-substituted phenylpyrazoles can be prepared by the method shown in Scheme 26. Conversion of the 5-hydroxy pyrazole to its triflate (triflic anhydride, lutidine in dichloromethane) or bromide (POBr₃) followed by palladium Suzuki cross-coupling with an apppropriately substituted phenylboronic acid should then afford 5-substituted pyrazoles. Conversion of this intermediate to the 4-bromo derivative followed by its carbonylation as described in Scheme 24 should then afford the appropriate ester which can be further afford the compounds of formula I. ##STR36##

1-Substituted-1,2,3-triazoles of the present invention can be prepared by the treatment of an appropriately substituted azide with a variety of dipolarophiles (Tetrahedron 1971, 27, 845 and J. Amer. Chem. Soc. 1951, 73, 1207) as shown in Scheme 27. Typically a mixture of regioisomers are obtained which can be easily separated and elaborated to the triazole carboxylic acids. Further transformations as previously described can then afford the compounds of the present invention. ##STR37##

1,2,4-Triazoles of the present invention can be obtained by the methodology of Huisgen et al (Liebigs Ann. Chem. 1962, 653, 105) by the cycloaddition of nitriliminium species (derived from the treatment of triethylamine and chloro hydrazone) and an appropriate nitrile dipolarophile (Scheme 28). This methodology provides a wide variety of 1,2,4 triazoles with a varied substitution pattern at the 1, 3, and 5 positions. ##STR38##

1,2,4 Triazoles can also be prepared by the methodology of Zecchi et al (Synthesis 1986, 9, 772) by an aza Wittig condensation (Scheme 29). ##STR39##

1,2,4-Triazoles wherein the --E--D(Q) substituent is at the 5-position of the triazole can be obtained as shown in Scheme 30. ##STR40##

1,3,4-Triazoles of the present invention can be obtained via the methodology of Moderhack et al (J. Prakt. Chem. 1996, 338, 169). As shown in Scheme 31, this reaction involves the condensation of a carbazide with an appropriately substituted commercially available thioisocyanate to form the cyclic thiourea derivative. Alkylation or nucleophilic displacement reactions on the thiono-urea intermediate can then afford a thio-alkyl or aryl intermediate which can be hydrolysed, oxidized and decarboxylated to the 5-H 2-thio-triazole intermediate which can be converted to the compounds of the present invention. Alternatively the thiono-urea intermediate can be oxidized directly to the 2-H triazole which can then be converted to the ester and modified as previously described. The thiono-urea intermediate can also be oxidized to the sulfonyl chloride by methods shown previously. ##STR41##

The imidazole core shown in Scheme 32 can be prepared by the condensation of 3-cyanoaniline with n-butylglyoxylate to afford the imine which can then be treated with TosylMIC in basic methanol to afford the desired imidazole compound. Coupling of the ester under standard conitions then affords a variety of analogs which then can be further manipulated to afford e.g. the benzylamine or the benzamidines. ##STR42##

Compounds of the present invention wherein AB is a biphenylamine or similar amine may be prepared as shown in Scheme 33. 4-Bromoaniline can be protected as Boc-derivative and coupled to a phenylboronic acid under Suzuki conditions (Bioorg. Med. Chem. Lett:. 1994, 189). Deprotection with TFA provides the aminobiphenyl compound. Other similar amines wherein A and/or B are heterocycles can be prepared by the same method using appropiately substituted boronic acids and arylbromide. The bromoaniline can also be linked to the core ring structures first as described above, and then undergo a Suzuki reaction to give the desired product. ##STR43##

Compounds of the present invention wherein A--B is A--X--Y can be prepared like the piperazine derivative shown in Scheme 34. ##STR44##

Scheme 35 shows how one can couple cyclic groups wherein X═NH, O, or S. ##STR45##

When B is defined as X--Y, the following description applies. Groups A and B are available either through commercial sources, known in the literature or readily synthesized by the adaptation of standard procedures known to practioners skilled in the art of organic synthesis. The required reactive functional groups appended to analogs of A and B are also available either through commercial sources, known in the literature or readily synthesized by the adaptation of standard procedures known to practioners skilled in the art of organic synthesis. In the tables that follow the chemistry required to effect the coupling of A to B is outlined.

                                      TABLE A                                      __________________________________________________________________________     Preparation of Amide, Ester, Urea, Sulfonamide and                             Sulfamide linkages between A and B.                                                           then the   to give the                                                                  reactive                                                                                    following product                         Rxn. No.                                                                             if A contains:                                                                            substituent of Y is:                                                                       A--X--Y:                                          __________________________________________________________________________     1    A--NHR.sup.2 as a                                                                        ClC(O)--Y  A--NR.sup.2 --C(O)--Y                                         substituent                                                           2       a secondary NH                                                                               ClC(O)--Y                                                                                A--C(O)--Y                                              as part of a                                                                   ring or chain                                                         3       A--OH as a                                                                                     ClC(O)--Y                                                                              A--O--C(O)--Y                                           substituent                                                           4       A--NHR.sup.2 as a                                                                     ClC(O)--CR.sup.2 R.sup.2a --Y                                                              A--NR.sup.2 --C(O)--CR.sup.2 R.sup.2a --Y                    substituent                                                           5       a secondary NH                                                                               ClC(O)--CR.sup.2 R.sup.2a --Y                                                       A--C(O)--CR.sup.2 R.sup.2a --Y                                as part of a                                                                   ring or chain                                                        6       A--OH as a                                                                                     ClC(O)--CR.sup.2 R.sup.2a --Y                                                    A--O--C(O)--CR.sup.2 R.sup.2a --Y                              substituent                                                          7       A--NHR.sup.3 as a                                                                     ClC(O)NR.sup.2 --Y                                                                           A--NR.sup.2 --C(O)NR.sup.2 --Y                              substituent                                                          8       a secondary NH                                                                               ClC(O)NR.sup.2 --Y                                                                    A--C(O)NR.sup.2 --Y                                         as part of a                                                                   ring or chain                                                        9       A--OH as a                                                                                     ClC(O)NR.sup.2 --Y                                                                  A--O--C(O)NR.sup.2 --Y                                      substituent                                                          10     A--NHR.sup.2 as a                                                                      ClSO.sub.2 --Y                                                                                     A--NR.sup.2 --SO.sub.2 --Y                             substituent                                                         11     a secondary NH                                                                                ClSO.sub.2 --Y                                                                              A--SO.sub.2 --Y                                        as part of a                                                                   ring or chain                                                       12     A--NHR.sup.2  as a                                                                     ClSO.sub.2 --CR.sup.2 R.sup.2a --Y                                                          A--NR.sup.2 --SO.sub.2 --CR.sup.2 R.sup.2a                                   --Y                                                             substituent                                                         13     a secondary NH                                                                          ClSO.sub.2 --CR.sup.2 R.sup.2a --Y                                                         A--SO.sub.2 --CR.sup.2 R.sup.2a --Y                           as part of a                                                                   ring or chain                                                       14     A--NHR.sup.2  as a                                                                         ClSO.sub.2 --NR.sup.2 --Y                                                                  A--NR.sup.2 --SO.sub.2 --NR.sup.2 --Y                      substituent                                                         15     a secondary NH                                                                          ClSO.sub.2 --NR.sup.2 --Y                                                                     A--SO.sub.2 --NR.sup.2 --Y                                 as part of a                                                                   ring or chain                                                       16     A--C(O)Cl                                                                                     HO--Y as a                                                                                A--C(O)--O--Y                                                                  substituent                                   17     A--C(O)Cl                                                                                     NHR.sup.2 --Y as a                                                                      A--C(O)--NR.sup.2 --Y                                                            substituent                                   18     A--C(O)Cl                                                                                     a secondary NH                                                                       A--C(O)--Y                                                                          as part of a                                                                   ring or chain                                 19     A--CR.sup.2 R.sup.2a C(O)Cl                                                             HO--Y as a                                                                                      A--CR.sup.2 R.sup.2a C(O)--O--Y                                                substituent                                   20     A--CR.sup.2 R.sup.2a C(O)Cl                                                             NHR.sup.2 --Y as a                                                                            A--CR.sup.2 R.sup.2a C(O)--NR.sup.2 --Y                                          substituent                                   21     A--CR.sup.2 R.sup.2a C(O)Cl                                                             a secondary NH                                                                             A--CR.sup.2 R.sup.2a C(O)--Y                                                        as part of a                                                                   ring or chain                                 22     A--SO.sub.2 Cl                                                                                 NHR.sup.2 --Y as a                                                                     A--SO.sub.2 --NR.sup.2 --Y                                                       substituent                                   23     A--SO.sub.2 Cl                                                                                 a secondary NH                                                                      A--SO.sub.2 --Y                                                                     as part of a                                                                   ring or chain                                 24     A--CR.sup.2 R.sup.2a SO.sub.2 Cl                                                         NHR.sup.2 --Y as a                                                                           A--CR.sup.2 R.sup.2a SO.sub.2 --NR.sup.2                                  -- Y                                                                                  substituent                                   25     A--CR.sup.2 R.sup.2a SO.sub.2 Cl                                                          a secondary NH                                                                          A--CR.sup.2 R.sup.2a SO.sub.2 --Y                                                   as part of a                                                                   ring or chain                                  __________________________________________________________________________

The chemistry of Table A can be carried out in aprotic solvents such as a chlorocarbon, pyridine, benzene or toluene, at temperatures ranging from -20° C. to the reflux point of the solvent and with or without a trialkylamine base.

                                      TABLE B                                      __________________________________________________________________________     Preparation of ketone linkages between A and B.                                               then the reactive                                                                        to give the                                           Rxn. No.                                                                             if A contains:                                                                           substituent of Y is:                                                                     following product A--X--Y                            __________________________________________________________________________     1    A--C(O)Cl BrMg--Y   A--C(O)--Y                                            2      A--CR.sup.2 R.sup.2a C(O)Cl                                                             BrMg--Y              A--CR.sup.2 R.sup.2a.sub.2 C(O)--Y        3      A--C(O)Cl                                                                                      BrMgCR.sup.2 R.sup.2a --Y                                                            A--C(O)CR.sup.2 R.sup.2a --Y                      4      A--CR.sup.2 R.sup.2a C(O)Cl                                                             BrMgCR.sup.2 R.sup.2a --Y                                                                   A--CR.sup.2 R.sup.2a C(O)CR.sup.2 R.sup.2a                                 --Y                                                   __________________________________________________________________________

The coupling chemistry of Table B can be carried out by a variety of methods. The Grignard reagent required for Y is prepared from a halogen analog of Y in dry ether, dimethoxyethane or tetrahydrofuran at 0° C. to the reflux point of the solvent. This Grignard reagent can be reacted directly under very controlled conditions, that is low temeprature (-20° C. or lower) and with a large excess of acid chloride or with catalytic or stoichiometric copper bromide dimethyl sulfide complex in dimethyl sulfide as a solvent or with a variant thereof. Other methods available include transforming the Grignard reagent to the cadmium reagent and coupling according to the procedure of Carson and Prout (Org. Syn. Col. Vol. 3 (1955) 601) or a coupling mediated by Fe(acac)₃ according to Fiandanese et al. (Tetrahedron Lett., (1984) 4805), or a coupling mediated by manganese (II) catalysis (Cahiez and Laboue, Tetrahedron Lett., 33(31), (1992) 4437).

                  TABLE C                                                          ______________________________________                                         Preparation of ether and thioether linkages between A and B                                       then the reactive                                                                           to give the                                    Rxn.                              followingent of                              No.    if A contains:                                                                                 Y is:               product A--X--Y                     ______________________________________                                         1     A--OH        Br--Y        A--O--Y                                        2        A--CR.sup.2 R.sup.2a --OH                                                                    Br--Y               A--CR.sup.2 R.sup.2a O--Y           3        A--OH                Br--CR.sup.2 R.sup.2a --Y                                                            A--OCR.sup.2 R.sup.2a --Y                  4        A--SH                Br--Y                                                                                       A--S--Y                             5        A--CR.sup.2 R.sup.2a --SH                                                                    Br--Y               A--CR.sup.2 R.sup.2a S--Y           6        A--SH                Br--CR.sup.2 R.sup.2a --Y                                                            A--SCR.sup.2 R.sup.2a --Y                  ______________________________________                                    

The ether and thioether linkages of Table C can be prepared by reacting the two components in a polar aprotic solvent such as acetone, dimethylformamide or dimethylsulfoxide in the presence of a base such as potassium carbonate, sodium hydride or potassium t-butoxide at temperature ranging from ambient temperature to the reflux point of the solvent used.

                  TABLE D                                                          ______________________________________                                         Preparation of --SO-- and --SO2-- linkages from                                thioethers of Table 3.                                                                                         and it is oxidized                                               and it is oxidized                                                                             with m-chloroper-                                              with Alumina (wet)/                                                                           benzoic acid (Satoh                                 if the            Oxone (Greenhalgh,                                                                       et al., Chem. Lett.                          Rxn.  starting        Synlett, (1992) 235)                                                                     (1992) 381), the                               No.    material is:                                                                                the product is:                                                                                product is:                                ______________________________________                                         1    A--S--Y      A--S(O)--Y    A--SO.sub.2 --Y                                2        A--CR.sup.2 R.sup.2a S--Y                                                               A--CR.sup.2 R.sup.2a S(O)--Y                                                                       A--CR.sup.2 R.sup.2a SO.sub.2 --Y        3        A--SCR.sup.2 R.sup.2a --Y                                                                A--S(O)CR.sup.2 R.sup.2a --Y                                                                      A--SO.sub.2 CR.sup.2 R.sup.2a            ______________________________________                                                                         --Y                                       

The thioethers of Table C serve as a convenient starting material for the preparation of the sulfoxide and sulfone analogs of Table D. A combination of wet alumina and oxone can provide a reliable reagent for the oxidation of the thioether to the sulfoxide while m-chloroperbenzoic acid oxidation will give the sulfone.

                                      TABLE E                                      __________________________________________________________________________     Methods of Preparing Group E                                                   Rxn                                                                               Q    D is to be                                                                             then a transformation that may be used is:                     __________________________________________________________________________     1  --CN --C(═NH)NH2                                                                         ##STR46##                                                     2  --CN --CH2NH2                                                                                ##STR47##                                                     3  --CO2H                                                                              --CH2NH2                                                                                ##STR48##                                                     4  --CO2H                                                                              --NH2                                                                                   ##STR49##                                                     __________________________________________________________________________

In Table E several methods of transforming a functional group Q into group D of Formula 1 are shown. While not all possible functional groups for Q and D are listed and the synthetic methods suggested are not comprehensive, Table E is meant to illustrate strategies and transformations available to a practitioner skilled in the art of organic synthesis for preparing compounds of Formula 1. In reaction 1 of Table E the transformation of a nitrile into an amidine by the Pinner methodology is shown; in reaction 2 the direct reduction of a nitrile by a hydride reducing agent to a methylene amine is illustrated. In reaction 3, the utility of a carboxylic acid, which may be readily derived from its ester or a nitrile if necessary, in the preparation of a methylene amine is shown. This synthetic route is exceptionally flexible because of the several stable intermediates prepared en route to the final product. As outlined, formation of an activated analog, such as the mixed anhydride, allows for the mild reduction of the acid to the methylene alcohol, this may in turn be transformed into a leaving group by sulfonylation or halogenation or protected with a suitable protecting group to be transformed later in the synthesis as the chemistry demands. Once the methylene alcohol is so activated, displacement by an efficient nitrogen nucleophile, such as azide anion, can again provide another suitably stable analog, --the methylene azide--which may be used as a protected form of the methylene amine or transformed directly into the methylene amine group by reduction. Reaction 4 addresses the problem of appending the amine functionality directly through a bond to group E of Formula 1. Once again, the carboxylic acid provides a convenient entre into this selection for group D. The well-know Curtius rearrangement is illustrated here; an activated acid analog can be used to form an acyl azide which upon thermal decomposition is rearranged to the corresponding isocyanate. The isocyanate intermediate may then be captured as a stable carbamate by the addition of a suitable alcohol and further heating. This carbamate can be used as a stable protecting group for the amine or cleaved directly to the desired D. Alternatively, it may be convenient to quench the isocyanate intermediate with water to give the amine directly.

Other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments which are given for illustration of the invention and are not intended to be limiting thereof.

EXAMPLES Fluoro-methylsulfone Intermediate 4-amino-3-fluoro-2'-methylsulfonyl-[1,1']-biphenyl, hydrochloride

Part A: Preparation of 4-bromo-N-t-butoxycarbonyl-2-fluoroaniline.

Sodium hydride (1.16 g, 60%, 29 mmol) was added to a 0° C. solution of 4-bromo-2-fluoro aniline (5.01 g, 26 mmol) in dry DMF (75 mL). The ice bath was removed and the reaction was stirred at room temperature for 1 h. Di-t-butyl dicarbonate (6.33 g, 29 mmol) was added, and the reaction was heated at 65° C. for 17 h. The reaction was quenched dropwise with H₂ O, then extracted 4 times with H₂ O. The first two aqueous extracts were combined and extracted twice with EtOAc. The organic extracts were combined, dried over Na₂ SO₄, filtered and evaporated. The crude product was taken up in a mixture of CH₂ Cl₂, CHCl₃, and EtOAc and filtered to remove a purple impurity, then concentrated and chromatographed on silica gel (30% CHCl₂ /hexanes) to yield an orange solid (4.76 g, 62%). ¹ HNMR(DMSO)δ: 9.07 (bs, 1H), 7.57 (td, 1H, J=8.7, J'=2.2), 7.49 (dd, 1H, J=10.2, J'=2.2), 7.30 (dt, 1H, J=8.8, J'=1.1), 1.42 (s, 9H)ppm.

Part B: Preparation of 4-(t-butoxycarbonylamino)-3-fluoro-2'-methylthio-[1,1']-biphenyl.

A flask containing a mixture of 4-bromo-N-t-butoxycarbonyl-2-fluoroaniline (6.44 g, 22 mmol), 2-(methylthio)phenylboronic acid (6.00 g, 36 mmol), aq. sodium carbonate (2.0 M, 36 mL, 72 mmol), tetrabutylammonium bromide (360 mg, 1.1 mmol), and bis(triphenylphosphine)palladium(II) chloride in benzene (180 mL) was evacuated twice under brief high vacuum, filled with argon, and heated at reflux for 5 h. After cooling to room temperature, the layers were separated, and the aqueous layer was extracted with EtOAc. The organic extracts were combined, dried over Na₂ SO₄, filtered, and evaporated. The crude product was chromatographed on silica gel (0-30% EtOAc/hexanes) to yield the desired product (6.50 g, 88%). ¹ HNMR(CHCl₃)δ: 8.14 (bt, 1H, J=8.1), 7.30 (m, 2H), 7.17 (m, 4H), 6.75 (bs, 1H), 2.37 (s, 3H), 1.54 (s, 9H)ppm.

Part C: Preparation of 4-(t-butoxycarbonylamino)-3-fluoro-2'-methylsulfonyl-[1,1']-biphenyl.

4-(t-Butoxycarbonylamino)-3-fluoro-2'-methylthio-[1,1']-biphenyl (6.50 g, 19.5 mmol) was dissolved in CH₂ Cl₂ (150 mL) and cooled to 0° C. m-CPBA (14.8 g, 57-86%) was added and the reaction stirred at room temperature for 3 h. The reaction was extracted with sat. sodium sulfite, and the aqueous layer was extracted with CH₂ Cl₂. The organic extracts were combined, dried over Na₂ SO₄, filtered, and evaporated. The crude product was chromatographed on silica gel (20-30% EtOAc/hexanes) to yield the desired product (6.92 g, 97%). ¹ HNMR(CHCl₃)δ: 8.22 (dd, 2H, J=7.7 J'=1.5), 7.64 (td, 1H, J=7.3, J'=1.5), 7.56 (td, 1H, J=7.7 J'=1.5), 7.35 (dd, 1H, J=7.3, J'=1.5), 7.30 (dd, J=11.7, J'=2.2), 7.17 (d, 1H, J=8.8), 6.82 (bs, 1H), 2.69 (s, 3H), 1.55 (s, 9H)ppm.

Part D: Preparation of 4-amino-3-fluoro-2'-methylsulfonyl-[1,1']-biphenyl, hydrochloride.

4-(t-Butoxycarbonylamino)-3-fluoro-2'-methylsulfonyl-[1,1']-biphenyl (1.04 g, 2.8 mmol) was dissolved in HCl/dioxane (4.0 M, 10 mL) and stirred 19 h. A solid was triturated with Et₂ O and filtered to yield a white solid (813 mg, 95%). ¹ HNMR(DMSO)δ: 8.03 (dd, 1H, J=8.0, J'=1.4), 7.69 (td, 1H, J=7.7, J'=1.1), 7.59 (t, 1H, J=7.4), 7.36 (d, 1H, J=7.3), 7.12 (d, 1H, J=12.4), 6.94 (m, 2H), 2.78 (s, 3H)ppm.

EXAMPLES 1 AND 2 1-(3-amidinophenyl)-2-[[(2'-aminosulfonyl-[1,1']-biphen-4-yl)-aminocarbonyl]pyrrole, trifluoroacetic acid salt (Example 1) and 1-(3-amidinophenyl)-2-[[(2'-tert-butylaminosulfonyl-[1,1']-biphen-4-yl)-aminocarbonyl pyrrole, trifluoroacetic acid salt (EXAMPLE 2)

Part A. Preparation of 1-(3-cyanophenyl) pyrrole.

3-aminobenzonitrile (47.45 g, 0.401 mol) and 58.4 g (0.441 mol, 59.5 ml) of 2,5-dimethoxytetrahydrofuran were dissolved in 200 ml of acetic acid and heated to reflux over night. The solution was allowed to cool to room temperature and diluted with 250 ml of ethylacetate and was washed 3 times with brine (200ml) and then by a solution of saturated aq sodium carbonate (200 ml). The organics were dried over magnesium sulfate and filtered through a plug of silica gel. The volatiles were removed in vacuo and the residue was recrystallized from methanol to yield the title compound as a beige solid (62.82 g, 93%) MS (H₂ O --CI) 169 (M+H)⁺.

Part B. Preparation of 1-(3-cyanophenyl) pyrrole-2-carboxaldehyde.

Phosphorous oxychloride, over the course of 15 minutes, was added to dimethylformamide (14.02 g, 191.84 mmol, 14.1 ml) at 0° C. The mixture was warmed to room temperature and stirred for 15 minutes; the solution was again cooled to 0° C. followed by the addition of 100 ml of 1,2 dichloroethane. A solution of 1-(3-cyanophenyl) pyrrole (29.33 g, 191.84 mmol) in 250 ml of 1,2 dichloroethane was added slowly via an addition funnel and the mixture heated to reflux for 15 minutes. The solution was cooled to room temperature and 86.55 g (1.05 mol) of sodium acetate was added and the solution heated to reflux for 15 minutes. The solution was diluted with 250 ml of ethyl acetate and the organics washed with brine then saturated aq sodium carbonate (250 ml). The organics were dried over magnesium sulfate, filtered through a plug of silica gel and the volatiles removed in vacuo. The product was recrystallized from ethyl acetate to yield 28.4 g (83%) of the title compound. MS (NH₃ --CI) 214 (M+NH₄)⁺.

Part C. Preparation of 1-(3-cyanophenyl) pyrrole-2-carboxylic acid.

To a cooled (0° C.) solution of 1-(3-cyanophenyl) pyrrole-2-carboxaldehyde (5.14g, 26.20 mmol) in 300 ml of 1:1 acetone/water was added potassium permanganate (12.42 g, 78.60 mmol) over a period of 15 minutes and the reaction was allowed to warm to room temperature. After consumption of the starting material, 10.90 g (104.8 mmol) of sodium bisulfite was added and the solution made acidic with 10% HCl. The solution was filtered through a plug of celite, diluted with ethyl acetate and washed with 200 ml of brine. The organics were dried over magnesium sulfate, filtered and dried in vacuo. The organics were recrystallized from methanol to yield the title compound (4.11 g, 74%) as a pale white solid. MS (ESI) 211.2 (M-H)⁻.

Part D. Preparation of 1-(3-cyanophenyl)-2-[[(2'-tert-butylaminosulfonyl-[1,1']-biphen-4-yl)-aminocarbonyl] pyrrole.

To a solution of l-(3-cyanophenyl) pyrrole-2-carboxylic acid (2.77 g, 13.05 mmol) in 50 ml of anhydrous DMF was added triethylamine (1.98 ml, 19.58 mmol), benzotriazole-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (8.66 g, 19.58 mmol) and (2 '-N-tert-butylaminosulfonyl-[1,1']-biphen-4-yl)-amine (6.03 g, 19.84 mmol) and heated to 50° C. overnight. The solution was diluted with ethyl acetate and washed repeatedly with brine. The organic layer was dried over magnesium sulfate and the volatiles removed in vacuo. The residue was subjected to flash chromatography purification with 3:2 hexane/ethyl acetate and the volatiles removed in vacuo to yield 1.9 g (29%) of the title compound. MS (NH₃ --CI) 516 (M+NH₄)⁺.

Part E. Preparation of 1-(3-amidinophenyl)-2-[[(2'-aminosulfonyl-[1,1']-biphen-4-yl)-aminocarbonyl] pyrrole, trifluoroacetic acid salt (Example 1) and 1-(3-amidinophenyl)-2-[[(2'-tert-butylaminosulfonyl-[1,1']-biphen-4-yl)-aminocarbonyl] pyrrole, trifluoroacetic acid salt (Example 2).

1-(3-Cyanophenyl)-2-[[(2'-tert-butylaminosulfonyl-[1,1']-biphen-4-yl)-aminocarbonyl] (0.37 g, 0.74 mmol) of pyrrole was added to a solution of 60 ml of anhydrous methyl acetate and anhydrous methanol (0.30 ml, 7.4 mmol) and cooled in an ice water bath. Gaseous HCl was bubbled in for 15 minutes, the solution stoppered and allowed to stir overnight at room temperature. The volatiles were removed in vacuo. The residue was dried under high vacuum for 1 hr. The residue was then dissolved in 100 ml of anhydrous methanol and combined with 0.43 g (4.45 mmol) of ammonium carbonate and stirred overnight at room temperature. The volatiles were removed in vacuo and the residue was purified by preparative HPLC (C18 reverse phase column, elution with a H₂ O/CH₃ CN gradient with 0.5% TFA) to yield 1-(3-amidinophenyl)-2-[[(2'-aminosulfonyl-[1,1']-biphen-4-yl)-aminocarbonyl] pyrrole, trifluoroacetic acid salt (Example 1) as a white solid following lyophilization. MS (ESI) 460.3 (M+H)⁺ ; also isolated was 1-(3-amidinophenyl)-2-[[(2'-tert-butylaminosulfonyl-[1,1']-biphen-4-yl)-aminocarbonyl] pyrrole, trifluoroacetic acid salt (Example 2). MS (ESI) 516.4 (M+H)⁺.

EXAMPLE 3 1- (3-amidinophenyl) -2- [(2 '-aminosulfonyl- [1,1]-biphen-4-yl)-aminocarbonyl]-4-bromopyrrole, trifluoroacetic acid salt

Part A. Preparation of 1-(3-cyanophenyl)-2-formyl-4-bromo-pyrrole.

1-(3-Cyanophenyl) pyrrole-2-carboxaldehyde from Example 1, Part B (6.06 g, 30.89 mmol) was combined with 6.60 g (37.06 mmol) of N-bromosuccinimide in 150 ml of anhydrous THF and stirred at room temperature overnight. The residue was heated in CCl₄ and filtered. The residue was then dissolved in CHCl₃ /EtOAc, filtered through a silica gel plug and the volatiles removed. The residue was recrystallized from ethyl acetate to yield the title compound as a light brown solid (4.49 g, 53%). MS (NH₃ --CI) 292 (M+NH₄)⁺.

Part B. Preparation of 1-(3-amidinophenyl)-2-[[(2'-aminosulfonyl-[1,1']-biphen-4-yl)-aminocarbonyl]-4-bromopyrrole, trifluoroacetic acid salt.

Following the procedures described in Example 1, Parts C-E, 1-(3-cyanophenyl)-2-formyl-4-bromo-pyrrole was converted into the title compound as a white powder following HPLC purification. MS (ESI) 538.2 (M+H)⁺.

EXAMPLE 4 1-(3-anidinophenyl)-2-[[5- (2'-aminosulfonylphenyl)-1-yl) pyridin-2-yl]-aminocarbonyllpyrrole, trifluoroacetic acid salt

Part A. Preparation of 1-(3-cyanophenyl)-2-[[5-(2'-tert-butylaminosulfonylphenyl)-1-yl)pyridin-2-yl)aminocarbonyl] pyrrole.

1-(3-Cyanophenyl) pyrrole-2-carboxylic acid from Example 1, Part C (1.00 g, 4.7 mmol), oxalyl chloride (.61 ml, 7.06 mmol) and 3 drops of DNF were combined at room temperature in 50 ml of anhydrous CH₂ Cl₂ and stirred for 4 hours. The volatiles were removed in vacuo and the residue was dried under high vacuum for 1 hour. The residue was then dissolved in 50 ml of CH₂ Cl₂ followed by the addition of 4-dimethylaminopyridine (1.15 g, 9.4 mmol), the solution stirred at room temperature for 5 minutes followed by the addition of [5-(2'-aminosulfonylphenyl)-1-yl) pyridin-2-yl]-amine (1.44 g, 4.7 mmol) and stirred at room temperature overnight. The solution was filtered through a silica gel plug and the volatiles removed. The residue was purified by flash chromatography (1:2 hexane/EtOAc) to yield 0.84 g (36%) of the title compound as a tan solid. MS (ESI) 500.3 (M+H)⁺.

Part B. Preparation of 1-(3-amidinophenyl)-2-[[5-(2'-aminosulfonylphenyl)-1-yl) pyridin-2-yl]-aminocarbonyl]pyrrole, trifluoroacetic acid salt.

Following the procedures described in Example 1, Part E, 1-(3-cyanophenyl)-2-[[5-(2'-tert-butylaminosulfonylphenyl)-1-yl)pyridin-2-yl]aminocarbonyl]pyrrole was converted into the title compound as a white powder following HPLC purification. MS (ESI) 461.3 (M+H)⁺.

EXAMPLES 5 AND 6 1-Benzyl-3-[(2'-aminosulfonyl-[1,1'-biphen-4-yl)aminocarbonyl]-4-(3-amidinophenyl)pyrrole, trifluoroacetic acid salt (Example 5) and 1-benzyl-3-[(2'-tert-butylaminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-4-(3-amidinophenyl)pyrrole, trifluoroacetic acid salt (Example 6)

Part A: Preparation of ethyl 3-(3-cyanophenyl)propiolate.

To a solution of ethyl propiolate (25.0 g, 0.25 mol) in 750 mL of tetrahydrofuran at -78° C. was added n-butyllithium (102 mL of a 2.5 M solution in hexane, 0.25 mol) dropwise. After stirring at the same temperature for 1 h, zinc chloride (104.2 g, 0.76 mol) was added in 900 mL of tetrahydrofuran. The mixture was allowed to gradually warm to room temperature over 1 h. To this solution was added 3-iodobenzonitrile (29.2 g, 0.13 mol) and bis triphenylphosphine palladium (II) chloride (4.56 g, 6.5 mmol) and the resulting mixture was stirred at 50° C. overnight. To the mixture was added 150 mL of water and 150 mL of ether and the mixture was filtered through a celite pad. The filtrate was extracted 3 times with ether and the combined extracts were washed with brine, dried (MgSO₄) and filtered through a thick pad of silica gel. The solvents were removed in vacuo and the residue was recrystallized from hexane ethyl acetate to afford 8.8 g (35%) of the title compound as a tan solid. ¹ HNMR(CDCl₃) δ: 7.85 (s, 1H), 7.8 (d, 1H), 7.72 (d, 1H), 7.52 (t, 1H), 4.30 (q, 2H), 1.37 (t, 3H).

Part B: Preparation of 1-benzyl-3-carboethoxy-4-(3-cyanophenyl)-Δ³ -pyrroline.

To a solution of N-benzyl-N-(trimethylsilylmethyl)-aminomethyl methyl ether (12.25 g, 51.2 mmol) in 400 mL of methylene chloride at 0° C. was added ethyl 3-(3-cyanophenyl)propiolate (6.79 g, 34.1 mmol) followed by trifluoroacetic acid (0.20 mL, 2.6 mmol). The mixture was allowed to warm to room temperature and was stirred for 16 h. The reaction mixture was washed with saturated aqueous NaHCO₃ and brine, dried over K₂ CO₃, filtered through a large pad of silica gel and concentrated in vacuo. The residue was purified by flash chromatography (elution with 5:1 hexanes/ethyl acetate) to afford 3.2 g (28%) of the title compound. MS (ESI) 333.4 (M+H)⁺.

Part C: Preparation of 1-benzyl-3-[(2'-tert-butylaminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-4-(3-cyanophenyl)-Δ³ -pyrroline.

To a solution of (2'-tert-butylaminosulfonyl-[1,1']-biphen-4-yl)-amine (1.10 g, 3.6 mmol) in 50 mL of methylene chloride at room temperature was added trimethylaluminum (6.6 mL of a 2.0 M solutiion in toluene, 13.2 mmol) dropwise. The solution was stirred (30 min) until gas evolution had ceased followed by the addition of 1-benzyl-3-carboethoxy-4-(3-cyanophenyl)-Δ³ -pyrroline (1.0 g, 3.0 mmol) in 5 mL of methylene chloride. The resulting solution was stirred at 40° C. for 2 h, cooled to room temperature and quenched with saturated aq NH₄ Cl. The mixture was diluted with ethyl acetate, washed with water and brine, dried (MgSO₄) and concentrated in vacuo. The residue was purified by flash chromatography (elution with 4:1 hexane/ethyl acetate) to afford 0.58 g (34%) of the title compound. MS (ESI) 591.5 (M+H)⁺.

Part D: Preparation of 1-benzyl-3-[(2'-tert-butylaminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-4-(3-cyanophenyl)pyrrole.

To a solution of 1-benzyl-3-[(2'-tert-butylaminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-4-(3-cyanophenyl)-Δ³ -pyrroline (0.47 g, 0.8 mmol) in 20 mL of benzene was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (0.27 g, 1.2 mmol) and the resulting mixture was stirred at 70° C. for 16 h. The mixture was cooled and filtered and concentrated in vacuo. The residue was purified by flash chromatography (elution with 5:1 hexane/ethyl acetate) to afford 0.25 g (53%) of the title compound. MS (ESI) 589.6 (M+H)⁺.

Part E: Preparation of 1-benzyl-3-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-4-(3-amidinophenyl)pyrrole, trifluoroacetic acid salt (Example 5) and 1-benzyl-3-[(2'-tert-butylaminosulfonyl-[1,1-biphen-4-yl)aminocarbonyl]-4-(3-amidinophenyl)pyrrole, trifluoroacetic acid salt (Example 6).

A solution of 1-benzyl-3-[(2'-tert-butylaminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-4-(3-cyanophenyl)pyrrole (0.25 g, 0.42 mmol) in 50 mL of anhydrous methanol was cooled to 0° C. Anhydrous HCl gas was bubbled through the solution for about 30 min (until solution saturated). The flask was sealed and allowed to stand for 16 h at 0° C. The reaction mixture was concentrated in vacuo . The resulting solid was dissolved in 20 mL of anhydrous methanol, ammonium carbonate (0.20 g, 2.1 mmol) was added, and the mixture was allowed to stir at room temperature for 24 h. The reaction mixture was concentrated in vacuo and purified by prep HPLC (C18 reverse phase column, elution with a H₂ O/CH₃ CN gradient with 0.5% TFA) to afford 120 mg (40%) of 1-benzyl-3-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-4-(3-amidinophenyl)pyrrole, trifluoroacetic acid salt (Example 5) as a white powder following lyophilization. MS (ESI) 550.3 (M+H)⁺. The preparation also afforded 40 mg (13%) of 1-benzyl-3-[(2'-tert-butylaminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-4-(3-amidinophenyl)pyrrole, trifluoroacetic acid salt (Example 6) as a white powder following lyophilization. MS (ESI) 606.5 (M+H)⁺.

EXAMPLES 7 AND 8 1-(3-amidinophenyl)-4-[(2'-aminosulfonyl-[1,1'-biphen-4-yl)aminocarbonyl]-imidazole (Example 7) and 1-(3-amidinophenyl) -4- [(2 ¹ -tert-butylaminosulfonyl- [1,1']-biphen-4-yl)aminocarbonyl]-imidazole (Example 8)

Part A: Preparation of 4-[(2'-tert-butylaminosulfonyl-(1,1']-biphen-4-yl)aminocarbonyl]-imidazole

To a suspension of 4-imidazolecarboxylic acid (168 mg, 1.5 mmol) in CH₃ CN (30 mL) was added thionyl chloride (714 mg, 6 mmol), and the resulting mixture was heated at 80° C. for 2 hours. After removal of volatiles, a yellow residue reacted with 4-[(o-SO₂ -t-Bu)-phenyl]aniline (304 mg, 1 mmol) in pyridine (10 mL) at room temperature for 24 hours. Evaporation of the pyridine gave a residue which was dissolved in EtOAc and washed with water, brine, and dried over MgSO4. Concentration and purification by column chromatography of the crude material provided the title compound (378 mg, 95% yield). ¹ HNMR(CD₃ OD) δ: 8.10 (dd, J=7.7 Hz, 1.1 Hz, 1H), 7.79 (d, J=3.7 Hz, 2H), 7.76 (d, J=8.4 Hz, 2H), 7.58 (td, J=7.7 Hz, J=1.5 Hz, 1H), 7.49 (dd, J=8.1 Hz, J=1.5 Hz, 1H), 7.45 (d, J=8.4 Hz, 2H), 7.34 (dd, J=7.7 Hz, J=1.5 Hz, 1H), 1.06 (s, 9H); LRMS: 399.3 (M+H)⁺.

Part B: Preparation of 1-(3-cyanophenyl)-4-[(2'-tert-butylaminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-imidazole

4-[(2'-tert-Butylaminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-imidazole was heated with 3-fluorobenzonitrile (121 mg, 1 mmol) in the presence of K₂ CO₃ in DMF at 100° C. for 8 hours to give the title compound in almost quantitative yield. ¹ HNMR(acetone-d₆)δ: 9.47 (s, 1H), 8.39 (d, J=1.5 Hz, 1H), 8.34 (d, J=1.5 Hz, 1H), 8.25 (d, J=1.5 Hz, 1H), 8.15-8.10 (m, 1H), 8.02 (d, J=8.4 Hz, 2H), 7.88-7.79 (m, 2H), 7.65 (td, J=7.3 Hz, J=1.5 Hz, 1H), 7.56 (dd, J=7.7 Hz, J=1.5 Hz, 1H), 7.50 (d, J=8.4 Hz, 2H), 7.38 (dd, J=8.4 Hz, J=1.5 Hz, 1H), 2.80 (s, 1H), 1.03 (s, 9H); LRMS: 500.1 (M+H)⁺.

Part C: Preparation of 1-(3-amidinophenyl) -4- [(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-imidazole (Example 7) and 1-(3-amidinophenyl)-4-[(2'-tert-butylaminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-imidazole (Example 8)

1-(3-Cyanophenyl)-4-[(2'-tert-butylaminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-imidazole was further subjected to a Pinner reaction by standard procedures to give Examples 7 (309 mg, 62% yield) and 8 (67 mg, 12% yield).

For Example 7: ¹ HNMR(CD₃ OD)δ:8.32 (d, J=1.4 Hz, 2H), 8.12 (s, 1H), 8.10 (d, J=8.1 Hz, 1H), 8.08 (dd, J=7.7 Hz, J=1.4 Hz, 1H), 7.88-7.81 (m, 2H), 7.78 (d, J=8.4 Hz, 2H), 7.61 (td, J=7.7 Hz, J=1.5 Hz, 1H), 7.52 (td, J=7.7 Hz, J=1.5 Hz, 1H), 7.44 (d, J=8.4 Hz, 2H), 7.35 (dd,. J=7.3 Hz, J=1.1 Hz, 1H); ¹³ C NMR (CD₃ OD)δ: 167.59, 162.59, 143.08, 141.63, 139.32, 138.97, 138.68, 137.58, 137.33, 133.72, 132.94, 132.44, 131.62, 131.28, 128.72, 128.66, 128.49, 127.66, 122.94, 122.12, 121.00; ESMS: 461.3 (M+H)⁺ ; HRMS: 461.1387 (obs.), 461.1396 (calcd.).

For Example 8: ¹ HNMR(CD₃ OD)δ: 8.33 (s, 2H), 8.12 (s, 1H), 8.10 (dd, J=8.4 Hz, J=1.5 Hz, 1H), 8.05 (dd, J=8.1 Hz, J=2.2 Hz, 1H), 7.88-7.80 (m, 3H), 7.79 (d, J=8.4 Hz, 2H), 7.61 (td, J=7.7 Hz, J=1.5 Hz, 1H), 7.53 (td, J=7.7 Hz, J=1.2 Hz, 1H), 7.47 (d, J=8.4 Hz, 2H), 7.35 (dd, J=7.3 Hz, J=1.5 Hz, 1H), 1.02 (s, 9H); ¹³ C NMR (CD₃ OD)δ: 167.58, 162.57, 143.51, 141.65, 139.02, 138.68, 138.68, 137.30, 133.89, 133.05, 132.44, 131.64, 131.52, 128.72, 129.53, 128.77, 128.50, 127.65, 122.96, 122.12, 120.99, 55.06, 30.11; ESMS: 517.4 (M+H)⁺ ; HRMS: 517.2025 (obs.), 517.2022 (calcd.); Anal.: (C₂₇ H₂₈ N₆ O₃ S₁ +1.35TFA+0.17HCI+0.6 H₂ O) C, H, N, S, F, Cl.

EXAMPLE 9 1-(3-amidinophenyl)-2-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-imidazole

Part A: Preparation of 1-(3-cyanophenyl)imidazole

3-Fluorobenzonitrile (4.84 g, 40 mmol) was heated with imidazole (2.72 g, 40 mmol) in the presence of K₂ CO₃ in DMF at 100° C. for 8 hours to give the title compound as a white solid in quantitative yield. ¹ HNMR(CDCl₃)δ: 7.89 (s, 1H), 7.70 (d, J=0.8 Hz, 1H), 7.68-7.58 (m, 3H), 7.30 (d, J=1.0 Hz, 1H), 7.26 (s, 1H); LRMS: 170 (M+H)⁺.

Part B: Preparation of methyl 1-(3-cyanophenyl)imidazol-2-yl carboxylate

1-(3-Cyanophenyl)imidazole (1.52 g, 9 mmol) was slowly treated with n-BuLi (1.6 M, 6.3 mL) in THF (60 mL) at -78° C. for 40 minutes and was then slowly quenched with chloromethylformate (942 mg, 10 mmol) at this temperature. The resulting mixture was stirred at -78° C. and warmed to room temperature over 2 hours and then poured into water and ethyl acetate. The organic layer was separated and washed with water, brine, and dried over MgSO₄. After removal of the ethyl acetate the residue was purified by column chromatography with ethyl acetate and methylene chloride (1:1) to afford the title compound (1.33 g, 65%) as a white solid. ¹ HNMR(CDCl₃)δ: 7.80-7.77 (m, 1H), 7.65-7.61 (m, 3H), 7.33 (s, 1H), 7.20 (s, 1H); LRMS: 228 (M+H)⁺.

Part C: Preparation of 1-(3-cyanophenyl)-2-[(2'-tert-butylaminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-imidazole

To a stirred solution of 4-[(o-SO₂ tBu)-phenyl]aniline (304 mg, 1 mmol) in CH₂ Cl₂ (20 mL) was slowly added trimethylaluminum (2M in hexane, 1 mL) at 0° C. and the resulting mixture was warmed to room temperature over 15 minutes. After addition a solution of methyl 1-(3-cyanophenyl)imidazol-2-yl carboxylate in CH₂ Cl₂ (5 mL) and the resulting mixture was refluxed for 2 hours. The mixture was quenched with water, diluted with ethyl acetate and filtered through Celite. The organic layer was separated, washed with water, and brine and dried over MgSO₄. After removal of the ethyl acetate, a residue was purified by column chromatography with ethyl acetate and methylene chloride (1:1) to afford the title compound (260 mg, 52%) as a white solid. ¹ HNMR(CDCl₃)δ: 9.41 (s, 1H), 8.15 (dd, J=7.7 Hz, J=1.5 Hz, 1H), 7.78 (dd, J=7.3 Hz, J=1.1 Hz, 1H), 7.74-7.57 (m, 6H), 7.55 (td, J=7.7 Hz, J=1.1 Hz, 1H), 7.49 (dd, J=8.8 Hz, J=1.8 Hz, 2H), 7.29 (dd, J=8.1 Hz, J=1.5 Hz, 1H), 7.28 (d, J=0.8 Hz, 1H), 7.22 (d, J=0.8 Hz, 1H), 3.64 (s, 1H), 0.99 (s, 9H); LRMS: 500.1 (M+H)⁺.

Part D: Preparation of 1-(3-amidinophenyl)-2-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-imidazole

1-(3-Cyanophenyl)-2-[(2'-tert-butylaminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-imidazole was subjected to the Pinner reaction to form the title compound (120 mg, 50%): ¹ HNM(CD₃ OD)δ: 8.08 (dd, J=7.7 Hz, J=1.1 Hz, 1H), 7.91-7.88 (m, 2H), 7.83 (dd, J=8.4 Hz, J=1.5 Hz, 1H), 7.74 (t, J=8.0 Hz, 1H), 7.65 (d, J=8.4 Hz, 2H), 7.58 (dd, J=7.3 Hz, J=1.1 Hz, 1H), 7.50 (s, 2H), 7.39 (d, J=8.4 Hz, 2H), 7.32 (s, 1H), 7.30 (dd, J=7.3 Hz, J=1.1 Hz, 1H); ESMS: 461 (M+H)⁺.

EXAMPLE 10 1-(3-amidinophenyl)-3-methyl-5-[(2'-arminosulfonyl- [1,1']-biphen-4-yl)aminocarbonyl]-pyrazole, trifluoroacetic acid

Part A: Preparation of ethyl 1-(3-bromophenyl)-3-methyl-pyrazol-5-yl carboxylate and ethyl 1-(3-bromophenyl)-5-methyl-pyrazol-3-yl carboxylate

2-Bromophenylhydrazine hydrochloride (6.5 g, 0.029 mol) was added in portions to a ethanolic solution of 3-methoxy-trichloroacetylcrotonate (Fischer et. al. Synthesis 1991, 83). The reaction mixture was refluxed for 48 h cooled and concentrated. The residue was dissolved in ethyl acetate (100 mL) and washed with HCl (1N, 50 mL), brine (50 mL) and dried (magnesium sulfate). Evaporation afforded an oil which was subjected to silica gel column chromatography (hexane:ethylacetate, 6:1) to afford ethyl 1-(3-bromophenyl)-5-methyl-pyrazol-3-yl carboxylate (3.73 g) and ethyl ethyl 1-(3-bromophenyl)-3-methyl-pyrazol-5-yl carboxylate (3.65 g) as pure compounds. The pyrazole carboxylate obtained this way were used directly in part B.

Part B: Preparation of ethyl 1-(3-cyanophenyl)-3-methyl-pyrazol-5-yl carboxylate

Ethyl 1-(3'bromophenyl)-3-methyl-pyrazol-5-yl carboxylate (2.3 g) was dissolved in N-methyl-pyrrolidinone (4 mL) and to this solution was added CuCN (1 g). The reaction mixture was refluxed for 2 h then stirred at room temperature overnight. The mixture was quenched with water (100 mL) and the organics were extracted with ethylacetate (2×100 mL) and dried (magnesium sulfate). Silica gel column chromatography (hexane:ethylacetate, 3:1) then afforded the title compound (0.59 g). ¹ HNMR(CDCl₃)δ: 7.76 (t, 1H), 7.70 (dd,1H), 7.58 (t,1H), 6.86 (s, 1H), 4.3 (q, 2H), 2.36 (s, 3H), 1.31 (t, 3H)ppm; IR (neat), 2230, 1728, 1586, 1540, 1494, 1438, 1298, 1242, 1106, 1046, 760, 682 cm¹⁻. Chemical Ionization mass spectrum m/z (rel. intensity) 256 (M+H, 100).

Part C: Preparation of 1-(3-cyanophenyl)-3-methyl-pyrazol-5-yl carboxylic acid

Ethyl 1-(3-cyanophenyl)-3-methyl-pyrazol-5-yl carboxylate (0.55 g) was dissolved in THF (20 mL) and to this was added LiOH (0.5M, 5,6 mL). The reaction mixture was stirred at room temperature for 18 h then quenched with water (50 mL). The unreacted organics were extracted with ethylacetate (2×50 mL). The aqueous layer was acidified and extracted with ethylacetate (2×50 mL) dried (magnesium sulfate) and evaporated to afford pure acid. ¹ HNMR(DMSO d₆)δ: 8.02 (t, 1H), 7.91 (d, 1H), 7.82 (dd, 1H), 7.09 (t, 1H), 6.89 (s, 1H), 2.27 (s, 3H) ppm; IR (PEC) 2930, 2232, 1724, 1710, 1540, 1496, 1458, 1276, 1230, 1186, 1146, 1112, 900, 768, 754, 690 cm¹⁻ ; Chemical ionization mass spectum m/z (rel. intensity) 228 (M+H, 100).

Part D: Preparation of 1-(3-cyanophenyl)-3-methyl-5-[(2'-tert-butylaminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-pyrazole

To a dichloromethane solution (20 mL) of 1-(3-cyanophenyl)-3-methyl-pyrazol-5-yl carboxylic acid (0.2 g) was added oxalyl chloride (0.11 mL). The reaction mixture was stirred at room temperature for 2 h then to this solution was added 2-tert-butylsulfonamide-1-biphenyl aniline (0.27 g) and triethylamine (0.5 mL). The reaction mixture was stirred at room temperature for 24 h then quenched with water (50 mL) and the organics were extracted with ethylacetate(2×50 mL), washed with brine(50 mL) and dried(magnesium sulfate). Evaporation afforded an oil which was chromatographed on silica gel column (dichloromethane:MeOH, 9:1) to afford the title compound (0.45g). ¹ HNMR(CDCl₃)δ: 8.16 (d, 1H), 8.05 (s, 1H), 7.8 (d, 1H), 7.76 (d, 1H), 7.68 (d, 3H), 7.58 (m, 2H), 7.50 (md, 3H), 7.30 (d, 1H), 6.76 (s, 1H), 3.64 (s, 1H), 2.42 (s, 3H), 1.03 (s, 9H) ppm; IR(PEC), 3320, 2976, 2232, 1682, 1592, 1540, 1522, 1488, 1464, 1438, 1368, 1320, 1242, 1152, 1128, 758, 682, 608 cm¹⁻ ; Chemical ionization mass spectum m/z (rel intensity) 458 (M═H, 100).

Part E: Preparation of 1-(3-amidinophenyl)-3-methyl-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-pyrazole, trifluoroacetic acid

1-(3-Cyanophenyl)-3-methyl-5-[(2'-tert-butylaminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-pyrazole (0.39 g) was dissolved in a saturated HCl solution of anhydrous MeOH (20 mL). The reaction mixture was stirred at room temperature for 24 h then MeOH was evaporated. The residue was redissolved in MeOH (20 mL) and excess ammonium carbonate added. The reaction mixture was stirred at room temperature for 18 h. MeOH was evaporated and the residue was purified via HPLC to afford the desired compound as its TFA salt (0.15 g). ¹ HNMR(DMSO d₆)δ: 10.66 (s, 1H), 9.44 (s, 1.5H), 9.09 (s, 1.5H), 8.03(d, 1H), 7.97 (s, 1H), 7.83 (t, 1H), 7.75 (d, 1H), 7.70 (d, 2H), 7.62 (m, 2H), 7.37 (d, 2H), 7.32 (d, 1H), 7.27(s, 2H), 7.03 (s, 1H), 2.50 (s, 3H) ppm; IR (PEC) 3288, 1704, 1660, 1592, 1526, 1484, 1438, 1322, 1206, 1160, 762, 724 cm¹⁻ ; High resolution mass spectrum calcd. for C₂₄ H₂₂ N₆ O₃ S 475.155236, found 475.153767.

EXAMPLE 11 1-(3-amidinophenyl)-3-methyl-5-r(2'-aminosulfonyl-[1,1]'-biphen-4-yl)carbonylaminol-pyrazole, trifluoroacetic acid

Part A. Preparation of 5-amino-l-(3' cyanophenyl)-3-methylpyrazole.

3-aminocrotonitrile (1 g, 12.2 mmol) and 3-cyanophenyl hydrazine hydrochloride (2 g, 11.8 mmol) were combined and heated to reflux in 1:1 ethanol/acetic acid (20 mL) for 4 h. The reaction was concentrated and the residue basified with diluted NaOH and extracted with ethyl acetate. The crude product was purified by flash chromatography on silica gel using hexanes/ethyl acetate (4:1) as eluent to afford 1.2 g of a still impure amine. This amine was dissolved in dilute HCl and extracted with ethyl acetate. The aqueous layer was basified with NaOH and extracted with ethyl acetate and dried (MgSO₄) to afford 0.66 g (28%) of amine; ¹ HNMR(CDCl₃)δ: 7.97 (s,1H), 7.92 (m,1H), 7.57 (s+d, 2H), 5.51 (s,1H), 3.75 (s,2H), 2.23 (s,3H); MS (H₂ O/GC) m/z 199 (M+H⁺).

Part B. Preparation of 1-(3'cyanophenyl)-3-methyl-5-((4'-bromophenyl)carbonylamino)pyrazole.

To the product of part A (0.66 g, 3.3 mmol) in methylene chloride (20 mL) at 0° C. was added 2M trimethylaluminum (8.3 mL, 16.7 mmol) in heptane. The mixture was stirred for 15 minutes and methyl-4-bromobenzoate (0.72 g,3.3 mmol) was added. The reaction was stirred overnight. The reaction was quenched with 1N HCl and extracted with methylene chloride and dried (Na₂ SO₄). Recrystallization from methylene chloride/hexanes yielded 0.48 g (45%) of the title compound; ¹ HNMR(CDCl₃)δ: 7.86 (s,1H), 7.78 (d, J=7.69Hz, 1H), 7.67 (d,J=7.69Hz.sub., 1H), 7.63 (m,4H), 7.60 (m,1H), 6.52 (s,1H), 2.36 (s, 3H); MS (ESI) m/z 381.1-383.1 (M+H⁺).

Part C. Preparation of 1-(3-cyanophenyl)-3-methyl-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)carbonylamino]-pyrazole, trifluoroacetic acid.

A mixture of the above part B amide (0.4 g, 1 mmol), 2-(t-butylsulfonamide)-phenylboronic acid (0.38 g, 1.5 mmol), 2M Na₂ CO₃ (1.3 mL),toluene (10 mL) and ethanol(10 mL) was degassed with nitrogen and then tetrakistriphenylphosphine palladium (10 mg) was added. The reaction was heated to reflux overnight then cooled, filtered and concentrated. The residue was diluted with water and then extracted with ethyl acetate and dried (MgSO₄). The crude product was purified by flash chromatography on silica gel using hexanes/ethyl acetate (2:1) as eluent to afford 0.46 g (86%) of a foam; ¹ HNMR(CDCl₃) δ: 7.94 (m,5H), 7.63 (m,7H), 7.32 (d,J=7.7Hz, 1H), 6.55 (s,1H), 4.13 (s,1H), 2.39 (s,3H), 0.99 (s,9H); MS m/z 514.3 (M+H⁺).

Part D. Preparation of 1-(3-amidinophenyl)-3-methyl-5-[(2'-aminosulfonyl-[1,1]-biphen-4-yl)carbonylamino]-pyrazole, trifluoroacetic acid.

The product from part D was then subjected to the standard Pinner amidine sequence to obtain the desired benzamidine after preparative HPLC (acetonitrile/water, containing 0.05% TFA) as colorless crystals (44% yield). ¹ HNMR(DMSO-d₆)δ: 10.57 (s,1H), 9.43 (s,1.5H), 9.14 (s,1.5H), 8.07 (s,1H), 8.05 (m,1H), 7.94 (d,J=6.96Hz,1H), 7.89 (d,J=8.42Hz,2H), 7.76 (m,2H), 7.65 (m,2H), 7.53 (d,J=8.42Hz,2H), 7.39 (s,2H), 7.35 (m,1H), 2.29 (s,3H);MS (ESI) m/z 475.2 (M+H⁺); Analysis calculated for C₂₄ H₂₂ N₆ O₃ S₁ (TFA)1.4 (H20)1: C 49.36; H 3.93; N 12.89; found C 49.69; H 3.71; N 12.77.

EXAMPLE 12 1-(3-amidinophenyl)-3-methyl-5-(2'-(5"-CF₃ -tetrazolyl)-[1,1']-biphen-4-yl)aminocarbonyl)pyrazole

Part A. Preparation of 2-(5'-CF₃ -tetrazolyl)biphenylaniline.

To a cold (0° C.) CCl₄ (3 mL) solution of 2'-trifluoroacetanilide-1-nitro-biphenyl (0.15 g, 0.48 mmoL) was added triphenylphosphine (0.24 g, 0.97 mmol) and the reaction stirred cold for 0.15 min, allowed to warm to room temperature and then gently refluxed overnight. Evaporation of the solvent afforded a residue which was treated with hexane (20 mL) filtered and evaporated to afford crude chloroimine which was dissolved in acetonitrile (10 mL). To this solution was added sodium azide (0.038 g, 0.58 mmoL) and the reaction mixture was stirred at room temperature over night. Evaporation of the solvent followed by purification via silica gel flash chromatography (hexane/ethylacetate 4:1) afforded the desired nitro-biphenyltetrazole precursor (0.12 g) as a pale yellow solid. ¹ HNMR(CDCl₃) δ: 8.2 (d, 2H), 7.80 (t, 1H), 7.70 (t, 1H), 7.61 (d, 1H), 7.50 (d, 1H), 7.3 (d, 2H) ppm; Ammonia CI mass spectrum analysis m/z (rel. intensity) 353.0 (M+NH₄ ⁺ 100).

The above nitro biphenyl compound was then hydrogenated in ethanol (20 mL) over 10% Pd/C for 6 h to afford after filtration the title compound (0.11 g). ¹ HNMR(CDCl₃) δ: 7.70 (t, 1H), 7.59 (d, 1H), 7.50 (t, 1H), 7.40 (d, 1H), 6.8 (d, 2H0, 6.55 (d, 2H), 3.75 (bd, 2H) ppm; Ammonia CI mass spectrum analysis m/z (rel. intensity) 323 (M+NH₄ ⁺ 100).

Part B. Preparation of 1-(3-cyanophenyl)-3-methyl-5-(2'-(5"-CF₃ -tetrazolyl)-[1,1']-biphen-4-yl)aminocarbonyl)pyrazole.

The 2-(5'-CF₃ -tetrazolyl)-[1,1']-biphenylaniline was then coupled to the 1-(3-cyanophenyl)-3-methyl-pyrazole-5-carboxylic acid (0.09 g, 0.39 mmoL) via the acid chloride methodology described previously to afford the title compound (0.12 g) as a colorless solid after silica gel column chromatography (dichloromethane:methanol, 9.6:0.4); ¹ HNMR(CDCl₃) δ: 7.82 (s, 1H), 7.70 (m, 4H), 7.61 (m, 2H), 7.45 (m, 3H), 7.05 (d, 2H), 6.65 (s, 1H), 3.50 (d, 1H), 2.40 (s, 3H) ppm; Ammonia CI mass spectrum analysis m/z (rel. intensity) 532.0 (M+NH₄ ⁺, 100).

Part C. Preparation of 1-(3-amidinophenyl)-3-methyl-5-(2'-(5"-CF₃ -tetrazolyl)-[1,1']-biphen-4-yl)aminocarbonyl)pyrazole.

The product from part B was then subjected to the Pinner amidine reaction sequence as described previously to afford the title compound as colorless crystals after prep. HPLC (acetonitrile:water containing 0,05% TFA); ¹ HNMR(DMSOd₆) δ: 10.61 (s, 1H), 9.42 (s, 2H), 9.12 (s, 2H), 7.94 (s, 1H), 7.89 (d, 1H), 7.82 (t, 2H), 7.75 (m, 4H), 7.62 (d, 2H), 7.02 (s, 2H), 6.98 (s, 1H), 2.32 (s, 3H)ppm; ESI mass spectrum analysis m/z (rel. intensity) 532.4 (M+H, 100); High resolution mass spectrum calcd. for CHNFO 532.182116, found 532.18271

EXAMPLE 13 1-(3-amidinophenyl)-5-[(2¹ -aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-4-chloro-3-methyl-pyrazole, trifluoroacetic acid

Part A. Preparation of 4-chloro-1-(3'cyanophenyl)-3-methyl-5-((2'-t-butylaminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl)pyrazole.

Chlorination of methyl-1-(3'cyanophenyl)-3-methyl-pyrazole-5-carboxylate (255 mg, 1 mmol) with NCS (139 mg, 1.05 mmol) in refluxing acetonitrile (10 mL) for 3 hours gave the desired 4-chloropyrazole carboxylate in quantitative yield. ¹ HNMR(CDCl₃)δ: 7.72-7.70 (m, 2H), 7.65-7.54 (m, 2H), 4.31 (q, J=7.0 Hz, 2H), 2.35 (s, 3H), 1.28 (t, J=7.0, 3H); LRMS: 290 (M+H). The ester in dichloromethane (5 mL) was added to a pretreated dichloromethane (20 mL) solution of 2'-t-butyl-sulfonamide-biphenylaniline and trimethylaluminum (2M in hexane, 1 mL) at 0° C. and the resulting mixture was warmed to room temperature over 15 minutes then refluxed for 3 hours. The mixture was quenched with water, extracted with CH₂ Cl₂ (200 mL), filtered through Celite. The organic layer was separated, washed with water, and brine and dried over MgSO₄. After removal of the CH₂ Cl₂, a residue was purified by column chromatography with ethylacetate and methylene chloride (1:1) to afford the title compound (330 mg, 60.3%) as a white solid. ¹ HNMR(CDCl₃): δ: 8.38 (s, 1H), 8.17 (dd, J=8.7, J=1.5 Hz, 1H), 7.78 (d, J=1.5 Hz, 1H), 7.73-7.69 (m, 2H), 7.67 (d, J=8.4 Hz, 2H), 7.60 (d, J=7.7 Hz, 1H), 7.55 (dd, J=7.7 Hz, J=1.5 Hz, 1H), 7.52 (d, J=8.7 Hz, 2H), 7.51-7.48 (m, 1H), 7.29 (dd, J=7.3 Hz, J=1.5 Hz, 1H), 3.62 (s, 1H), 2.40 (s, 3H), 1.03 (s, 9H); LRMS: 548 (M+H).

Part B. Preparation of 1-(3-amidinophenyl)-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-4-chloro-3-methyl-pyrazole, trifluoroacetic acid

The product of part A was then subjected to the standard Pinner amidine sequence to afford after preparation HPLC and purification with CH₃ CN--H₂ O-TFA the title compound (350 mg). ¹ HNMR(CD₃ OD) δ: 8.09 (dd, J=8.1 Hz, J=1.4 Hz, 1H), 8.00 (t, J=1.8 Hz, 1H), 7.81 (td, J=7.7 Hz, J=1.9 Hz, 2H), 7.71 (d J=8.1 Hz, 1H), 7.64 (d, J=8.4 Hz, 2H), 7.59 (dd, J=7.3 Hz, J=1.4 Hz, 1H), 7.52 (td, J=7.7 Hz, J=1.4 Hz, 1H), 7.42 (d, J=8.4 Hz, 2H), 7.32 (dd, J=8.4 Hz, J=1.4 Hz, 1H), 2.36 (s, 3H); ESMS:509.1 (M+H)⁺.

EXAMPLE 14 1-(3-amaidinophenyl)-5-((2'-t-butylaminosulfonyl-[1,1']-biphen-4-yl) arainocarbonyl)-3-trifluoromethylpyrazole

Part A. Preparation of 1-(3-cyanophenyl)-5-methyl-3-trifluoromethylpyrazole.

1,1,1-Trifluoro-2,4-pentanedione (1.35 mL, 11.2 mmol) was combined with 3-bromophenylhydrazine hydrochloride (3 g, 13.4 mmol) in glacial acetic acid (20 mL), 2-methoxyethanol (10 mL) and heated to reflux 2 h. The solvents were removed in vacuo and the residue was dissolved in ethyl acetate. The ethyl acetate solution was washed successively with dilute HCl, sat'd NaHCO₃, brine, and dried (MgSO₄). The crude material was purified by flash chromatography on silica gel using hexanes/ethyl acetate (8:1) as eluent. The product was an 88/12 mixture of the two isomers with the desired 5-methylpyrazole isomer pre-dominating. This mixture was combined with 1-methyl pyrrolidine (7 mL) and copper cyanide (1.3 g, 14.5 mmol) and heated to reflux overnight. The reaction was cooled, diluted with ethyl acetate and filtered. The filtrate was washed with water and brine and dried (MgSO₄). Purification by flash chromatography on silica gel afforded the desired 5-methylpyrazole isomer (0.66 g, 24%); ¹ HNMR(CDCl₃) δ: 7.81 (d, J=1.8Hz, 1H), 7.77 (m,2H), 7.67 (t, J=8.06Hz, 1H), 6.52 (s, 1H), 2.42 (s, 3H); MS (NH3) m/z 252.1 (M+H⁺), 269.2 (M+NH4+).

Part B. Preparation of 1-(3-cyanophenyl)-5-hydroxymethyl-3-trifluoromethylpyrazole.

To the compound obtained in part A (0.65 g,2.59 mmol), n-bromosuccinimide (0.48 g, 2.7 mmol), and benzoyl peroxide (20 mgs) were added and the reaction mixture was heated to reflux in carbon tetrachloride (20 mL) for 6 h. The reaction was cooled, filtered, and concentrated to yield the crude bromide. The bromide was combined with 1:1 dioxane/water (20 mL) and calcium cabonate (0.46 g, 4.6 mmol) and heated on a steam bath for 6 h. The reaction was cooled, filtered and the filtrate concentrated. The aqueous residue was extracted with ethyl acetate and dried (MgSO₄). The crude product was purified by flash chromatography on silica gel using hexanes/ethyl acetate (1:1) as eluent to afford a yellow solid (0.31 g, 44%); ¹ HNMR(CDCl₃) δ: 8.07 (s,1H), 8.01 (dd, J=2.2,8.05Hz, 1H), 7.77 (d, J=7.7Hz, 1H), 7.68 (t, J=8.05Hz, 1H), 6.76 (s,1H), 4.72 (d,J=5.85Hz, 2H), 2.02 (t,J=5.86Hz, 1H); MS (NH3) m/z 268.1 (M+H⁺), 285 (M+NH₄ ⁺).

Part C. Preparation of 1-(3-cyanophenyl)-3-trifluoromethylpyrazole-5-carboxylic acid.

To the above alcohol (0.18 g, 0.67 mmol) was added acetonitrile (5 mL), sodium periodate(0.3 g, 1.4 mmol) in water (5 mL), and one crystal of ruthenium(III)chloride hydrate. The reaction was stirred for 18h at room temperature. The reaction was filtered and concentrated. The aqueous residue was extracted with ethyl acetate and dried (MgSO₄) to give 0.17 g (89.9%) of acid. ¹ HNMR(CDCl₃ +DMSO-d₆)δ: 7.82 (d,J=1.47Hz), 7.78 (dd, J=8.0,1.47Hz, 1H), 7.63 (t,J=7.3,8.42, 1H), 7.29 (s,1H); MS (ESI--) m/z 280.2 (M--H).

Part D. Preparation of 1-(3-cyanophenyl)-5-((2'-t-butylaminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl)-3-trifluoromethylpyrazole.

To the acid (0.35 g, 1.2 mmol) in methylene chloride was added oxalyl chloride (0.15 mL, 1.7 mmol) and 2 drops of DMF. The reaction was stirred for 2 h at room temperature then concentrated in vacuo . The acid chloride was combined with 2'-t-butylsulfonamide-biphenylaniline (0.38 g, 1.25 mmol), methylene chloride (10 mL), and N,N-dimethylaminopyridine (0.38 g, 3.1 mmol). The reaction was stirred overnight at room temperature. The reaction was washed with dilute HCl, sat'd NaHCO₃, brine and dried (MgSO₄). The crude product was purified by flash chromatography on silica gel using hexanes/ethyl acetate (1:1) as eluent to afford 0.41 g (58%) of a yellow foam. ¹ HNMR(CDCl₃ +DMSO-d₆)δ: 9.88 (s,1H), 8.18 (dd,J=7.69,1.47Hz, 1H), 7.87 (d, J=1.83Hz, 1H), 7.79 (m,4H), 7.64 (m,3H), 7.50 (m,3H), 7.30 (d,J=7.3Hz,1H), 3.67 (s,1H),1.02 (s.9H); MS (ESI) m/z 590.14 (M+Na).

Part E. Preparation of 1-(3-amidinophenyl)-5-((2'-t-butylaminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl)-3-trifluoromethylpyrazole.

The product from part D was then subjected to the standard Pinner amidine sequence to obtain the title compound after preparative HPLC (acetonitrile/water, containing 0.05% TFA) as colorless crystals (46% yield). ¹ HNMR(DMSO-d₆)δ: 10.85 (s,1H), 9.47 (s,1.5H), 9.20 (s,1.5H), 8.05 (s,1H), 8.04 (dd, J=7.69,1.84Hz, 1H), 7.96 (m,2H), 7.82 (d, J=7.69Hz, 1H), 7.75 (s.1H), 7.68 (d,J=8.79Hz,2H), 7.62 (m,2H), 7.39 (d, J=8.43Hz, 2H), 7.32 (s+m,3H); MS (ESI) m/z 529.03 (M+H+); Analysis calculated for C₂₄ H₁₉ F₃ N₆ O₃ S₁ (TFA) 1.2 (H₂ 0) 1: C 46.40; H 3.27; N 12.30; found C 46.11; H 3.06; N 12.05.

EXAMPLE 15 1-(3-amidinophenyl)-4-methoxy-5-((2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl)-3-trifluoromethylpyrazole

Part A. Preparation of 1-(3-bromophenyl)-4-methoxy-5-methyl-3-trifluoromethylpyrazole.

3-Bromophenylhydrazine (9.4 g, 50.5 mmol) and trifluoroacetaldehyde hydrate (8.7 g, 75 mmol) were heated to 100° C. for 1 h. The reaction was cooled, diluted with methylene chloride, washed with brine and dried (MgSO₄). To the crude hydrazone was added 40% aqueous pyruvic aldehyde (22.6 g, 126 mmol), MgSO₄ (13 g), butyl acetate (150 mL) and several drops of acetic acid and the reaction was heated to reflux overnight. The reaction was filtered and concentrated. The residue was dissolved in 1N NaOH and extracted with diethyl ether. The aqueous layer was acidified with HCl and extracted with ethyl acetate and dried (MgSO₄). A crude orange solid (11.3 g, 70%) was collected. To the solid was added acetone (50 mL), K₂ CO₃ (7.3 g, 53 mmol), and iodomethane (8.8 mL, 140 mmol) and the mixture was heated to reflux for 2 h. The reaction was filtered, concentrated and the crude product was purified by flash chromatography on silica gel using hexanes/ethyl acetate (4:1) as eluent to afford 6.9 g (60%) of yellow oil. ¹ HNMR(CDCl₃)δ: 7.65 (d,J=1.83Hz, 1H), 7.58 (dd,J=2.2,6.96Hz, 1H), 7.39 (s+m,2H), 3.85 (s,3H), 2.31 (s,3H); MS (H2O/GC) m/z 335-337 (M+H⁺).

Part B. Preparation of 1-(3-cyanophenyl)-4-methoxy-5-methyl-3-trifluoromethyl pyrazole.

1-(3-Bromophenyl)-4-methoxy-5-methyl-3-trifluoromethyl pyrazole (6.9 g, 20.6 mmol) and CuCN (2.8 g, 30.9 mmol) were combined in N-methylpyrrolidinone (12 mL) and heated to reflux for 18 h. The reaction was diluted with water and extracted with ethyl acetate. The organic layers were washed with water, brine and dried (MgSO₄). The product was purified by flash chromatography on silica gel using hexanes/ethyl acetate (4:1) as eluent to afford 4.2 g (72%) of yellow solid. ¹ HNMR(CDCl₃)δ: 7.79 (s,1H), 7.74 (m,2H), 7.66 (d,J=7.3Hz,1H), 3.86 (s,3H), 2.35 (s, 3H); MS (H₂ 0/GC) m/z 282 (M+H+); IR (KBr) 2232, 1588, 1320, 1170, 1120, 804 cm⁻¹ ; Analysis calculated for C₁₃ H₁₀ F₃ N₃ O₁ : C 55.52; H 3.58; N 14.94; found C 55.44; H 3.76; N 14.95.

Part C. Preparation of 5-bromomethyl-l-(3-cyanophenyl)-4-methoxy-3-trifluoromethylpyrazole.

To the product of part B (2.65 g, 9.40 mmol) was added n-bromosuccinimide (1.76 g, 9.90 mmol), CC14 (15 mL) and benzoyl peroxide (10 mg). The reaction was heated to reflux for 4 h, then cooled and filtered. The crude bromide was dissolved in 1:1 dioxane/water (20 mL) and CaCO₃ (1.7 g, 16.9 mmol) was added. The reaction was stirred at room temperature overnight. The product was purified by flash chromatography on silica gel using hexanes/ethyl acetate (2:1) as eluent to afford 2.2 g (79%) solid. A sample was recrystallized from methylene chloride/hexanes. ¹ HNMR(CDCl₃)δ: 8.10 (m,1H), 8.05 (dd,J=8,1.46Hz, 1H), 7.74 (d,J=7.7Hz,1H), 7.66 (t,J=7.69Hz,1H), 4.67 (d,J=5.13Hz,2H), 3.95 (s,3H), 2.17 (t,J=5.13Hz, 1H); MS (ESI) m/z 288.2 (M+H+); Analysis calculated for C₁₃ H₁₀ F₃ N₃ O₂ : C 52.53; H 3.39; N 14.14; found C 52.35; H 3.21; N 14.13.

Part D. Preparation of 1-(3-cyanophenyl)-4-methoxy-3-trifluoromethylpyrazole-5-carboxylic acid.

To the product of part C (0.64 g, 2.2 mmol) in CH₃ CN (5 mL) at 0° C. was added sodium periodate (0.98 g, 4.5 mmol) in water (5 mL) followed by one crystal of ruthenium(III) chloride. The reaction was stirred cold for 30 minutes, then at room temperature for 30 minutes. The reaction was concentrated and partioned between ethyl acetate and dilute NaOH. The ethyl acetate layer was dried (MgSO₄), filterd and concentrated to afford the aldehyde (0.42 g,66%). The basic layer was acidified, extracted with ethyl acetate and dried (MgSO₄) to afford the carboxylic acid (0.16 g ,23%). To the aldehyde (0.42 g , 1.40 mmol) was added ethanol (50 mL), silver nitrate (0.48 g, 2.8 mmol), and 0.5N NaOH (12 mL). The reaction was stirred 3 h, then filtered through celite and concentrated. The aqueous layer was extracted with ethyl acetate and dried (MgSO₄) to yield the title compound (0.4 g, 91%). ¹ HNMR (CDCl₃ +DMSO-d₆)δ: 7.80 (m,3H), 7.61 (m, 1H), 4.01 (s, 3H).

Part E. Preparation of 1-(3-cyanophenyl)-4-methoxy-5-((2'-t-butylaminosulfonyl-[J,1l]-biphen-4-yl)aminocarbonyl)-3-trifluoromethylpyrazole-5-carboxylic acid.

To the acid of part D (0.44 g, 1.4 mmol) was added methylene chloride (15 mL), oxalyl chloride (0.17 mL, 1.9 mmol) and 2 drops of DMF. The reaction was stirred for 3 h then, concentrated. To the crude acid chloride was added 2'-t-butylsulfonamide-biphenylaniline (0.43 g, 1.4 mmol), methylene chloride (15 mL), and triethylamine (0.8 mL, 5.6 mmol). The reaction was stirred 18 h then, diluted with methylene chloride and washed with dilute HCl, sat'd NaHCO₃, brine and dried (MgSO₄) to yield 0.6 g (52%) foam. ¹ HNMR(CDCl₃)δ: 9.03 (s,1H), 8.18 (m,1H), 7.80 (s,1H), 7.78 (m,2H), 7.66 (d,J=8.79Hz,2H), 7.65 (m,1H), 7.56 (m,2H), 7.52 (d,J=8.79Hz, 2H), 7.27 (m,1H), 4.19 (s,3H), 1.03 (s, 9H); MS (ESI) m/z 598.4 (M+H⁺).

Part F. Preparation of 1-(3-amidinophenyl)-4-methoxy-5-((2'-aminosulfonyl-[1,1'-biphen-4-yl)aminocarbonyl)-3-trifluoromethylpyrazole.

The product from part D was subjected to the standard Pinner amidine sequence to obtain the desired benzamidine after preparative HPLC (acetonitrile/water, containing 0.05% TFA) as colorless crystals (46% yield). ¹ HNMR(DMSO-d₆)δ: 11.05 (s,1H), 9.49 (s,1.5H), 9.22 (s,1.5H), 8.03 (m,2H), 7.89 (m,3H), 7.65 (m+d,J=8.05Hz, 4H), 7.39 (m+d,J=8.40Hz,5H), 3.96 (s,3H); MS (ESI) m/z 559.4 (M+H+); Analysis calculated for C₂₅ H₂₁ F₃ N₆ O₄ S(TFA): C 48.22; H 3.31; N 12.50; found C 47.86; H 3.34; N 12.24.

EXAMPLE 16 1-(3-amidinophenyl)-3-methyl-5-(4,-(imdazol-1-yl-phenyl)aminocarbonyl)pyrazole

Part A. Preparation of 1-(4-aminophenyl)imidazole.

1-(4-Nitrophenyl)imidazole (5.0 g) and 200 mL of methanol were combined to form a solution at ambient temperature. The addition of a catalytic amount of 10% palladium on carbon turned the solution into a suspension. Placement of the reaction mixture under a hydrogen atmosphere initiated the reduction. The reaction proceeded overnight (15 h) at ambient temperature. Filtration through a celite pad separated out the catalyst. Concentration of the filtrate under reduced pressure gave the title product as a pale yellow solid (3.99 g). ¹ HNMR(DMSO d₆) δ: 7.95 (s, 1H), 7.45 (s, 1H), 7.18 (d, 2H), 6.99 (s, 1H), 6.60 (d, 2H), 5.25 (s, 2H) ppm. LRMS(GC/MS) m/z 160 (M+H, 100).

Part B. Preparation of N-(3-cyanophenyl)-3-methyl-5-(((4'-imidazol-1-yl)-phenyl)aminocarbonyl)pyrazole.

To 0.203 g of N-(3-cyanophenyl)-3-methyl-pyrazole 5-carboxylic acid and 10 mL dichloromethane was added oxalyl chloride and 2 drops of DMF. The reaction proceeded overnight. Concentration of the reaction mixture and placement under high vacuum gave the crude acid chloride which was then coupled to the product of part A under standard conditions to afford after standard purification techniques the title compound (0.118 g). ¹ HNMR(DMSO-d₆) δ: 10.73 (s, 1H) 9.35 (s, 1H) 8.13 (s, 1H) 7.95 (s, 1H) 7.90-7.60 (complex, 8H) 7.00 (s, 1H) 2.30 (s, 3H) ppm. LRMS(ESI) m/z 369.2 (M+H, 100). HRMS(NH₃ -CI) calc.369.146384, found369.145884.

Part C. Preparation of N-(3-amidinophenyl)-3-methyl-5-[((4,-imidazol-1-yl)-phenyl)aminocarbonyl]pyrazole.

Standard transformation of the benzonitrile obtained in part B to the benzamidine via the ethyl imidate converted 0.113 g of benzonitrile to 0.070 g of the benzamidine bis-TFA salt after HPLC purification. ¹ HNMR(DMSO-d₆): 10.65 (s, 1H) 9.40 (s, 2H) 9.00 (s, 2H) 8.19 (s, 1H) 7.90 (s 1H) 7.80-7.55 (complex,8H) 7.06 (s 1H) 7.00 (s 1H) 2.30 (s, 3H)ppm. LRMS(ESI) m/z 386.1 (M+H, 2) 193.7 (100). HRMS(FAB) calc.386.172933, found 386.173388

EXAMPLE 17 1-(3-amidinophenyl)-3-methyl-5-[(4'-(2"-sulfonylmethyl)phenoxyphenyl)aminocarbonyl]pyrazole

Part A. Preparation of 1-(3-cyanophenyl)-3-methyl-5-[(4'-(2"-sulfonylmethyl)phenoxyphenyl)aminocarbonyl[pyrazole.

Coupling of 4-(2'-sulfonylmethyl)phenoly-1-aminophenyl with 1-(3-cyano)phenyl-3-methyl-5-pyrazole carboxylic acid via standard acid chloride protocols described previously afforded the title compound; ¹ HNMR(CDCl₃) δ: 8.05 (d, 1H), 7.82 (s, 1H), 7.78 (d, 1H), 7.65 (d, 2H), 7.55 (m, 4H), 7.10 (d, 2H), 6.95 (d, 2H), 6.65 (s, 1H), 3.32 (s, 3H), 2.40 (s, 3H) ppm; Ammonia mass spectrum analysis m/z (rel. intensity) 490 (M+NH₄ ⁺, 100).

Part B. Preparation of 1-(3-amidinophenyl)-3-methyl-5-[(4'-(2"-sulfonylmethyl)phenoxyphenyl)aminocarbonyl]pyrazole

Subjecting the product obtained in part A to the Pinner amidine reaction sequence afforded after preparative HPLC (acetonitrile:water containing 0.05% TFA) the title compound as colorless crystals. ¹ HNMR(DMSO d₆) δ: 10.64 (s, 1H), 9.43 (s, 2H), 9.08 (s, 2H), 7.95 (m, 2H), 7.83 (d, 1H), 7.75 (d, 2H), 7.67 (m, 2H), 7.34 (t, 2H), 7.17 (d, 2H), 7.03 (s, 1H), 6.98 (d, 1H), 3.35 (s, 3H), 2.34 (s, 3H) ppm; ESI mass spectrum analysis m/z (rel. intensity) 490 (M+H, 100); high resolution mass spectrum calcd for CHNSO 490.153564, found 490.153759.

EXAMPLE 18 1-(3-amidinophenyl)-3-methyl-5- [(2N-anosulfonyl- [1,1']-biphen-4-yl)methylcarbonyl]-pyrazole

Part A. Preparation of 1-(3-cyanophenyl)-5-[(4'-bromophenyl)methylcarbonyl]-3-methylpyrazole.

To zinc dust (0.19 g, 2.9 mmol) in THF (3 mL) was added several drops of dibromoethane and the mixture was heated to reflux for 5 minutes, then cooled to 0° C. To the activated zinc was added 4-bromobenzyl bromide (0.59 g, 2.3 mmol) in THF (6 mL) dropwise over 5 minutes. The reaction was stirred at 0° C. for 2 h and then it was cannulated into a THF (5 mL) solution of LiCl (0.2 g, 4.7 mmol) and CuCN (0.21 g, 2.3 mmol) at -78° C. The mixture was warmed to -10° C. for 5 minutes, then cooled to -78° C. and the acid chloride of 1-(3-cyanophenyl)-5-carboxy-3-methylpyrazole (0.45 g, 1.98 mmol) in THF (5 mL) was added. The reaction was allowed to warm to room temperature overnight. The reaction was diluted with ethyl acetate and washed with sat'd NaHCO₃, brine and dried (Na₂ SO₄). The product was purified by flash chromatography on silica gel using hexanes/ethyl acetate (2:1) as eluent to afford 0.15 g (17%) solid: ¹ HNMR(CDCl₃)δ: 7.67 (dd, J=1.83, 6.96Hz, 1H), 7.62 (s, 1H), 7.54 (m,2H), 7.49 (d, J=8.42Hz, 2H), 7.13 (d, J=8.42Hz, 2H), 6.90 (s, 1H), 4.10 (s, 2H), 2.39 (s,3H); MS (NH3) m/z 380-382 (M+H)⁺, 397-399 (M+NH₄)⁺.

Part B. Preparation of 1-(3-cyanophenyl)-5-[2'-t-butylaminosulfonyl-[1,1']-biphen-4-yl)methylcarbonyl]-3-methylpyrazole.

A mixture of the bromide above (0.14 g, 0.37 mmol), 2M Na₂ CO₃ (1 mL), 2-t-butylsulfonimide boronic acid (0.13 g, 0.50 mmol) and 1:1 ethanol/toluene (15 mL) was degassed with nitrogen for 15 minutes. Tetrakis(triphenylphoshine) palladium (2 mg) was added and the reaction was heated to reflux for 18 h. The reaction was concentrated and the residue was taken up in ethyl acetate, washed with water and dried (MgSO₄). The product was purified by flash chromatography on silica gel using hexanes/ethyl acetate (2:1) as eluent to afford 0.19 g (100%) of a clear viscous oil: ¹ HNMR(CDCl₃)δ: 8.18 (dd, J=1.46,7.69Hz, 1H), 7.68 (m, 2H), 7.58 (m, 2H), 7.52 (d, J=8.40Hz, 2H), 7.51 (m, 2H), 7.34 (d, J=8.05Hz, 2H), 7.33 (m, 1H), 6.95 (s, 1H), 4.21 (s, 2H), 3.48 (s, 1H), 2.40 (s, 3H), 0.97 (s, 9H); MS (ESI) m/z 535.19 (M+Na)⁺.

Part C. Preparation of 1-(3-amidinophenyl)-3-methyl-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)methylcarbonyl]-pyrazole.

The title compound was obtained in 37% yield following the standard Pinner-amidine sequence outlined previously. ¹ HNMR(DMSO-d₆)δ: 9.39 (s, 1.5H), 9.03 (s, 1.5H), 8.03 (dd, J=7.32,1.83Hz, 1H), 7.85 (m, 2H), 7.68 (m, 2H), 7.59 (m, 2H), 7.44 (s, 1H), 7.36 (m, 7H), 4.34 (s, 2H),2.34 (s, 3H); MS (ESI) m/z 474.18 (M+H)⁺.

EXAMPLE 19 1-(3-amidinophenyl)-5-[(2 ¹ -aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-1,2,3-triazole

The title compound was obtained as colorless crystals from N-1(meta-cyanophenyl)-1,2,3-triazole-2-carboxylic acid (Sheehan et. al. J. Amer. Chem. Soc. 1951, 73, 1207) following the general method described previously. ¹ HNMR(DMSO d₆)δ: 10.9 (s,1H), 9.49 (bs,1.5H), 9.20 (bs, 1.5H),9.60 (s,1H), 8.11 (s,1H), 8.06-7.95 (m,3H), 7.88-7.80 (t, 1H), 7.69-7.56 (m,3H), 7.38 (d, 2H), 7.29 (bs, 3H) ppm; ESI mass spectral analysis m/z rel. intensity) 463 (M+H, 100); High resolution mass spectrum analysis calcd. for C₂₁ H₁₉ N₈ SO₃ 463.130084, found 463.129575.

EXAMPLE 20 1-(3-amidinophenyl)-5-((2'-trifluoromethyl-[1,1']-biphen-4-yl)aminocarbonyl)tetrazole, trifluoroacetic acid salt

Part A. Preparation of 1-(3-cyanophenyl)-5-[(4'-bromophenyl) aminocarbonyl3tetrazole.

4-Bromoaniline was dissolved in CH₂ Cl₂ (25 mL). Trimethylaluminum (2 M in heptane 7.0 mL, 14 mmol) was added slowly. The mixture was stirred at room temperature under N₂ for 15 min. Then, a solution of 1-(3-cyanophenyl)-5-carboethoxy-tetrazole (0.77 g, 3.16 mmol) in CH₂ Cl₂ (25 mL) was added (prepared in part A of Example 24). The mixture was stirred at room temperature over the weekend. The reaction mixture was quenched carefully with 1N HCl. It was diluted with CH₂ Cl₂ and washed with water and brine, it was dried over MgSO₄, concentrated, and chromatographed on silica gel (eluted with CH₂ Cl₂) to give 0.30 g of the desired product. ¹ HNMR(DMSO-d6) δ: 6.05 (q, 4H); 7.85 (t, 1H); 8.10 (t, 2H); 8.35 (s, 1H); 11.5 (s, 1H). MS (NH3-CI) 386 (M+NH4)⁺.

Part B. Preparation of 1-(3-cyanophenyl)-5-((2'-trifluoromethyl-[1,1']-biphen-4-yl)aminocarbonyl)tetrazole

The material from Part A (0.30 g, 0.813 mmol) and 2-trifluoromethyl phenylboronic acid (0.2 g, 1.06 mmol) were dissolved in EtOH/toluene (4.2 mL/10 mL). The mixture was stirred at room temperature and bubbled N₂ for 30 min. Then K₂ CO₃ (0.82 mL of 2 M, 1.63 mmol), tetrabutylammonium bromide (13 mg, 0.04 mmol) and tetrakis(triphenylphosphine)-palladium(0) (46 mg, 0.04 mmol) were added. The mixture was refluxed under N₂ for 4 hours. The reaction mixture was cooled and filter through celite. The solvent was removed. The residue was dissolved in EtOAc, washed with water and brine, it was dried over MgSO₄, concentrated and chromatographed on silica gel (eluted with CH₂ Cl₂) to give 0.35 g of the title compound. ¹ HNMR(CDCl₃)δ: 7.15 to 7.95 (m, 12H); 9.15 (s, 1H). MS (NH₃ -CI) 452 (M+NH₄)⁺.

Part C. Preparation of 1-(3-amidinophenyl)-5-((2'-trifluoromethyl-[1,1']-biphen-4-yl)aminocarbonyl)tetrazole, trifluoroacetic acid salt.

The material from part B was dissovled in 10 mL anhydrous CHCl₃ and 10 mL anhydrous CH₃ OH. The mixture was cooled in an ice-bath and HCl gas was bubbled-in until the solution was saturated. The reaction mixture was sealed and kept at refrigerator for 12 h. The solvent was removed and the solid was dried under vacuum. The solid was redissolved in 20 mL of anhydrous CH₃ OH and ammonium acetate (0.63 g, 10 eq) was added. The mixture was sealed and stirred at room temperature for 12 h. The solvent was removed. The solid was dissolved in CH₃ CN/H₂ O/TFA and purified by reversed phase HPLC to give 150.0 mg of the desired product. ¹ HNMR(DMSO-d6) δ: 7.30 to 8.25 (m, 12H); 9.20 (s, 1H); 9.50 (s, 1H); 11.55 (s, 1H). MS (ESI) 452.2 (M+H)⁺.

EXAMPLE 21 1-(3-amiainophenyl)-5-((2'-aminosulfonyl-3-chloro-[1,1']-biphen-4-yl)methylthio)tetrazole, trifluoroacetic acid salt

Part A. Preparation of 1-(3-cyanophenyl)-5-thio-tetrazole

m-Cyanophenylthioisocyanate (3.20 g, 20 mmol) was dissolved in 40 mL of CHC₃. The mixture was heated to dissolve the starting material and a solution of NaN₃ (2.64 g, 80 mmol) in 30 mL of H₂ O was added. The mixture was refluxed under N₂ for 1.5 h. The mixture was cooled and the two layers were separated. The aqueous layer was acidified with conc. HCl. The white precipitate was filtered and dried to give 3.33 g of the desired product. ¹ HNMR(acetone-d₆) δ: 7.86 (t, 1H); 7.97 (d, 1H); 8.38 (d, 1H), 8.53 (s, 1H).

Part B. Preparation of 2'-t-butylaminosulfonyl-4-bromomethyl-3-chloro-[1,1']-biphenyl.

2'-t-Butylaminosulfonyl-3-chloro-4-methyl-[1,1']-biphenyl was converted to the bromo-compound by reluxing in NBS/CCl₄.

Part C. Preparation of 1-(3-cyanophenyl)-5-((2'-t-butylaminosulfonyl-3-chloro-[1,1']-biphen-4-yl)methylthio)tetrazole.

1-(3-Cyanophenyl)-5-thio-tetrazole (0.22 g, 1.08 mmol) and 2'-t-Butylaminosulfonyl-4-bromomethyl-3-chloro-[1,1']-biphenyl (0.45 g, 1.08 mmol) were added together with 20 mL of THF. Triethylamine (0.15 mL, 1.08 mmol) aws added and the mixture was refluxed under N₂ for 30 min. The solvent was removed, the residue was dissolved in CH₂ Cl₂ and chromatographed on silica gel with 30% EtOAc in hexane to give 0.40 g white foam. ¹ HNMR(CDCl₃) δ: 1.03 (s, 9H); 3.58 (s, 1H); 4.82 (s, 2H); 7.26 (d, 1H); 7.37 (d, 1H); 7.53 (m, 3H); 7.75 (d, 2H); 7.82-7.92 (m, 3H), 8.16 (d, 1H). MS(ESI) 539.3 (M+H)⁺.

Part D. Preparation of 1-(3-amidinophenyl)-5-((2'-aminosulfonyl-3-chloro-[1,1']-biphen-4-yl)methylthio)tetrazole, trifluoroacetic acid salt

1-(3-cyanophenyl)-5-[(2¹ -t-butylaminosulfonyl-3-chloro-[1,1']-biphen-4-yl)methylthio]tetrazole (0.24 g, 0.45 mmol) was dissolved in 20 mL of CHCl₃ and 2 mL of anhydrous CH₃ OH. The mixture was cooled in an ice-bath and HCl gas was bubbled-in until the solution was saturated. The reaction mixture was sealed and stirred at room temperature for 12 h. The solvent was removed and the solid was dried under vacuum. The solid was redissolved in 10 mL of anhydrous CH₃ OH and ammonium acetate (0.21 g, 6 eq) was added. The mixture was sealed and stirred at room temperature for 12 h. The solvent was removed. The solid was dissolved in CH₃ CN/H₂ O/TFA and purified by reversed phase HPLC to give 0.11 g of the title compound. ¹ HNMR(DMSO-d₆) δ: 4.79 (s, 2H); 7.30-7.69 (m, 8H); 7.90 (t, 1H); 8.02 (m, 3H); 8.11 (s, 1H); 9.20 (s, 2H); 9.48 (s, 2H). MS(ESI) 500.2 (M+H)⁺.

EXAMPLES 22 AND 23 1-(3-amidinophenyl)-5-[(2'-aminosulfonyl-3-chloro-[1,1']-biphen-4-yl)methylsulfoxideltetrazole, trifluoroacetic acid salt (Example 22) and 1-(3-amidinophenyl)-5-[(2'-aminosulfonyl-3-chloro-[1,1']-biphen-4-yl)methylsulfonyl]tetrazole, trifluoroacetic acid salt (Example 23)

1-(3-amidinophenyl)-5-[(2'-aminosulfonyl-3-chloro-[1,1']-biphen-4-yl)methylthioltetrazole, trifluoroacetic acid salt (80.0 mg, 0.13 mmol) was dissovled in 10 mL of methanol. Oxone (0.32 g, 0.52 mmol) was added. The mixture was stirred at room temperature under N₂ for 72 h. The mixture was filtered and the solid was washed with methanol. The filtrate was concentrated and then dissolved in CH₃ CN/H₂ O/TFA and purified by reversed phase HPLC to give 48 mg of the the sulfoxide and 23 mg of the sulfone. ¹ HNMR(sulfoxide, CH₃ OH-d₄) δ: 5.08 (q, 2H); 7.25-7.32 (m, 4H); 7.50-7.63 (m, 4H); 7.85 (m, 2H); 8.00-8.10 (m, 3H). MS(ESI) 500.2 (M+H)⁺.sup.. 1 HNMR(sulfonyl,DMSO-d₆) δ: 5.37 (s, 2H); 7.30-7.69 (m, 7H); 7.82-8.10 (m, 5H); 8.20 (s, 1H); 9.18 (s, 2H); 9.52 (s, 2H). MS(ESI) 532.2 (M+H)⁺.

EXAMPLE 24 1- (3-amidinophenyl)-5-[(2¹ -aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]tetrazole, trifluoroacetic acid salt

Part A. Preparation of 1-(3-cyanophenyl)-5-carboethoxy-tetrazole.

3-aminobenzonitrile (5.0 g, 42.3 mmol) was dissolved in CH₂ Cl₂ (100 mL). Triethylamine (6.5 mL, 46.5 mmol) was added followed by ethyl oxalyl chloride (4.73 mL, 42.3 mmol). The mixture was stirred at room temperature under N₂ for 15 min. It was diluted with CH₂ Cl₂ and washed with water and brine. the CH₂ Cl₂ solution was dried over MgSO₄ and concentrated to a tan solid (6.33 g). The amide (3.00 g, 13.72 mmol) was then refluxed 20 h with a solution of triphenylphosphine (5.4 g, 20.58 mmol) in 50 mL of CCl₄. The solution was stirred at 0° C. for 15 min before the amide was added. The reaction mixture was cooled and hexane was added. The precipitate was filtered off. The filtrate was concentrated to a solid. It was then dissolved in 100 mL of CH₃ CN and NaN₃ (0.89 g, 1 eq) was added. The mixture was stirred at room temperature under N₂ for 12 h. The solvent was removed. The solid was dissolved in EtOAc and washed with water and brine. It was dried over MgSO₄ and concentrated, and chromatographed on silica gel(eluted with CH₂ Cl₂) to give 2.50 g of the desired product. ¹ HNMR(acetone-d₆) δ: 1.24 (t, 3H); 4.38 (q, 2H); 7.90 (t, 1H); 8.11 (m, 2H); 8.24 (s, 1H). MS(DCI-NH₃) 261 (M+NH₄)⁺.

Part B. Preparation of 1-(3-cyanophenyl)-5-[(2'-t-butylaminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]tetrazole.

2'-t-Butylaminosulfonyl-4-amino-[1,1']-biphenyl (0.25 g, 0.82 mmol) was dissolved in 10 mL of anhydrous CH₂ Cl₂, and trimethylaluminium (1.64 mL of 2.0 M solution in heptane) was added slowly. The mixture was stirred at room temperature under N₂ for 15 min, and 1-(3-cyanophenyl)-5-carboethoxy-tetrazole (0.20 g, 0.82 mmol) was added. The reaction mixture was stirred at room temperature under N₂ for 18 h. The reaction was quenched carefully with 0.1N aqueous HCl. It was diluted with CH₂ Cl₂ and washed with water and brine. The organic solution was then dried over MgSO₄, concentrated, and chromtographed on silica gel (5% EtOAc/CH₂ Cl₂) to give 0.22 g of the desired product. MS(ESI) 502.3 (M+H)⁺.

Part C. Preparation of 1-(3-amidinophenyl)-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]tetrazole, trifluoroacetic acid salt

The material from Part B was dissolved in 20 mL of anhydrous CHCl₃ and 5 ml of anhydrous CH₃ OH. The mixture was cooled in an ice-bath and HCl gas was bubbled-in until the solution was saturated. The reaction mixture was sealed and stirred at room temperature for 12 h. The solvent was removed and the solid was dried under vacuum. The solid was redissolved in 10 mL of anhydrous CH₃ OH and ammonium acetate (0.34 g, 10 eq) was added. The mixture was sealed and stirred at room temperature for 12 h. The solvent was removed. The solid was dissolved in CH₃ CN/H₂ O/TFA and purified by reversed phase HPLC to give 80.0 mg of the desired product. ¹ HNMR(DMSO-d₆) δ:7.28 (m, 3H); 7.37 (d, 2H); 7.60 (m, 2H); 7.78 (d, 2H); 7.89 (t, 1H); 8.02 (t, 2H); 8.15 (d 1H); 8.20 (s, 1H), 9.14 (s, 2H); 9.50 (s, 2H); 11.52 (s, 1H). MS (ESI) 463.3 (M+H)⁺.

Examples 25-48, shown in Table 1a below, were prepared using the above described procedures.

EXAMPLE 49 3-Methyl-1-(3-amidinophenyl)-5-(4'-(4"-chlorophenyl)thiasol-2'-yl)aminocarbonyl)pyrazole

Part A. Preparation of 3-methyl-1-(3-cyanophenyl)-5-(4'-(4"-chlorophenyl)thiazol-2'-ylaminocarbonyl)pyrazole.

1-(3-cyanophenyl)-3-methylpyrazole-5-carboxylic acid (70 mg, 0.31 mmol) was reacted with 2-amino-4-(4'-chlorophenyl)thiazole (168 mg, 0.8 mmol) in the presence of DMAP (191 mg, 1.5 mmol) and BOP reagent (benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, 442 mg, 1 mmol) in DMF (5 mL) at 60° C. for 16 h to give the title compound (100 mg, 77%).

Part B. Preparation of 3-methyl-1-(3-cyanophenyl)-5-(4'-(4"-chlorophenyl)thiazol-2'-ylaminocarbonyl)pyrazole.

A Pinner reaction under standard procedures was used to form the title compound (39 mg, 17%): ¹ HNMR (CD₃ OD)δ: 7.93 (d,J=1.8 Hz, 1H), 7.79-7.77 (m, 1H), 7.70 (t, J=7.7 Hz, 1H), 7.44 (s, 1H), 7.38 (d, J=8.4 Hz, 2H), 7.07 (s, 1H), 2.38 (s, 3H); HRMS: 437.0951 (M+H)⁺.

EXAMPLE 50 1-(3-amidino)phenyl-3-methyl-5-[(2'-trifluoromethylsulfide-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole

Part A. Preparation of 2'-trifluoromethylthio-1-aminobiphenyl

Palladium catalysed Suzuki cross-coupling methodology of 4-aminotrifluoromethylacetyl-phenylboronic acid with 2-bromo-1-trifluoromethylthio-benzene afforded 2'-trifluoromethylthio-1-aminotrifluoromethylacetyl-biphenyl in 72% yield; ¹ HNMR(CDCl₃)δ: 8.53 (bs, 1H), 7.78 (d, J=8 Hz, 1H), 7.62 (d, J=8 Hz, 2H), 7.48-7.60 (m, 1H), 7.29-7.46 (m, 5H) ppm; ¹⁹ F NMR (CDCl₃) δ: -42.5 (s, 3F) and -76.2 (s, 3F); Ammonia CI mass spectrum m/z (rel int.) 383 (M+NH₄ ⁺, 100) 366 (M+H, 100). Saponification (1N NaOH in methanol) then afforded the title compound in 80% yield; ¹ HNMR(CDCl₃) δ: 7.77 (d, J=8 Hz, 1H), 7.30-7.55 (m, 4H), 7.09 (d, J=4 Hz, 2H), 6.70 (d, J=8 Hz, 2H), 3.69-3.80 (bs, 2H) ppm; Ammonia CI mass spectrum m/z (rel. int.) 256 (M+H, 100); ¹⁹ F NMR (CDCl₃) δ: -42.5 ppm.

Part B. Preparation of 1-(3-cyanophenyl)-3-methyl-5-[(2'-trifluoromethylsulfide-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole

Coupling of the product obtained in part A with the pyrazole acid chloride as illustrated in Example 10 then afforded the desired coupled phenylnitrile analog in 75% yield; ¹ HNMR(CDCl₃) δ: 8.13 (bs, 1H), 7.70 (dd, J=1.8 & 7.4 Hz, 1H), 7.51 (m, 2H), 7.48 (t, j=7.7 Hz, 2H), 7.38 (t, J=7.6 Hz, 2H), 7.28 (m, 2H), 6.67 (s, 1H), 2.36 (s, 3H) ppm; ESI mass spectrum m/z (rel. int.) 501 (M+Na, 92), 479 (M+H, 100); ¹⁹ F NMR (CDCl₃) δ: -42.4 ppm.

Part C.

Following the Pinner amidation reaction protocol as illustrated for Example 10 afforded the desired benzamidine compound in 50% yield after preparative HPLC (reverse phase, CH₃ CN:water) as colorless crystals; ¹ HNMR(DMSO-d₆)δ: 10.7 (s, 1H), 9.43 (bs, 1.5H), 9.07 (bs, 1.5H), 7.98 (s, 1H), 7.89-7.65 (m, 8H), 7.58-7.49 (m, 2H), 7.35 (d, J=8 Hz, 2H), 7.04 (s, 1H), 2.37 (s, 1H) ppm; ESI mass spectrum m/z (rel. int.) 496 (M+H, 100); HRMS calcd for C₂₅ H₂₁ N₅ F₃ SO 496.141892, Found 496.142995.

EXAMPLES 51 AND 52 1-(3-amidino)phenyl-3-methyl-5-[(2'-trifluoromethylsulfoxide-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole (Example 51) and 1-(3-amidino)phenyl-3-methyl-5-[(2'-trifluoromethylsulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole (Example 52)

The product obtained in part C of Example 50 was subjected to oxidation with OXONE® (10 eq.) in methanol/water 9:1 to afford a mixture of the sulfoxide and sulfonyl products. Preparative HPLC (reverse phase, CH₃ CN:water) afforded pure sulfoxide in 45% yield (colorless crystals after lyophilization); ¹ HNMR(DMSO-d₆)δ: 9.40 (bs, 1.5H), 9.04 (bs, 2H), 8.08 (d, J=8 Hz, 1H), 7.96 (s, 1H), 7.84-7.68 (m, 8H), 7.50 (m, 3H), 7.04 (s, 1H), 2.35 (s, 3H) ppm; ESI mass spectrum m/z 512. The sulfonyl product was also obtained as colorless crystals in 15% yield (colorless crystals after lyophilization); ¹ HNMR(DMSO-d₆) δ: 9.43 (bs, 1.5H), 9.07 (bs, 2H), 8.23 (d, 1H), 7.99 (m, 1H), 7.98 (s, 1H), 7.89-7.69 (m, 7H), 7.55 (d, j=8 Hz, 1H), 7.26 (d, J=8 Hz, 1H), 7.04 (s, 1H), 2.37 (s, 2H) ppm; ESI mass spectum m/z 528.1.

EXAMPLE 53 1-(3-amidino)phenyl-3-methyl-5-[4'-(carboxymethyl)phenylaminocarbonyl]pyrazole

Methyl-4-amino-benzoate was coupled to the pyrazole acid chloride via the method illustrated for Example 10 to obtain the benzonitrile coupled product in quantitative yield. ¹ HNMR(CDCl₃) δ: 8.01 (d, J=8 Hz, 2H), 7.97 (s, 1H), 7.80 (s, 1H), 7.78-7.53 (m, 4H), 6.70 (s, 1H), 3.90 (s, 2H), 2.39 (s, 3H) ppm; ESI mass spectum m/z (rel. int.) 361 (M+H, 100); The nitrile was then subjected to the Pinner amidine reaction sequence as illustrated for Example 10 to obtain after preparative HPLC separation the desired product in 50% yield (colorless crystals); ¹ HNMR(DMSO-d₆)δ: 9.40 (bs, 1.5H), 9.18 (bs, 1.5H), 7.91 (m, 3H), 7.86-7.64 (m, 6H), 7.08 (s, 1H), 3.81 (s, 3H), 2.37 (s, 2H) ppm; ESI mass spectrum m/z (rel. int) 378 (M+H, 100); HRMS calcd for C₂₀ H₂₀ N₅ O₃ 378.156615, Found 378.158283.

EXAMPLE 54 1-(3-amidino)phenyl-3-methyl-5-[4'-(N,N-dimethylaminocarbonyl)phenylaminocarbonyl]pyrazole

The coupled benzonitrile pyrazole methyl ester obtained above was subjected to saponification (LiOH, THF/water) followed by acidification (1N HCl) to obtain the corresponding carboxylic acid product which was then coverted to the dimethyl amide derivative via its acid chloride. Following the Pinner amidine reaction protocols adopted for Example 10 then afforded the desired product as colorless crystals in 50% yield); ¹ HNMR(DMSO-d₆) δ: 10.7 (s, 1H), 9.40 (bs, 2H0, 9.04 (bs, 2H), 7.96 (s, 1H), 7.84-7.68 (m, 6H), 7.38 (d, J=8.0 Hz, 2H), 7.03 (s, 1H), 2.95 (bs, 6H), 2.36 (s, 3H) ppm; ESI mass spectrum m/z (rel. int.) 391 (M+H, 100).

EXAMPLE 55 1-(3-amidino)phenyl-3-methyl-5-[4'-(N,N-dimethylaminosulfonyl)phenylaminocarbonyl]pyrazole

Coupling of 4-amino-N,N-dimethylbenzene-sulfonamide with the pyrazole acid chloride obtained for Example 10 afforded the desired benzonitrile-pyrazole coupled product in 90% yield. ¹ HNMR(CDCl₃) δ: 8.09 (s, 1H0, 7.80-7.65 (m, 7H), 7.54 (m, 1H), 6.77 (s, 1H), 2.71 (s, 6H), 2.40 (s, 3H) ppm; Ammonia CI mass spectrum (rel. int) 410 (M+H, 100). Subjecting the nitrile obtained above to the Pinner amidine reaction protocol as illustrated for Example 10 afforded the desired product in 70% yield as colorless crystals following preparative HPLC (reverse phase, acetonitrile:water) purification. ¹ HNMR(DMSO-d₆) δ: 10.8 (s, 1H), 9.39 (bs, 1.5H), 9.17 (bs, 1.5H), 7.89 (m, 3H), 7.79 (m, 1H), 7.77-7.63 (m, 4H), 7.06 (s, 1H), 2.30 (s, 3H), 2.45 (s, 3H) ppm; ESI mass spectum m/z (rel. int) 426 (M+H, 100).

EXAMPLES 56 AND 57 1-(3-amidino)phenyl-3-methyl-5-[(4'-tert-butylaminosulfonylphenyl)aminocarbonyl]pyrazole (Example 56) and 1-(3-amidino)phenyl-3-methyl-5-[(4'-aminosulfonylphenyl)aminocarbonyl]pyrazole (Example 57)

Coupling of 4-amino-N-tert-butylbenzene-sulfonamide with the pyrazole acid chloride obtained for Example 10 afforded the desired coupled benzonitrile precursor in 80% yield. ¹ HNMR(CDCl₃) δ: 8.35 (bs, 1H), 7.77 (m, 4H), 7.71 (m, 1H), 7.69-7.64 (m, 3H), 7.53 (t, 1H), 6.89 (s, 1H), 2.39 (s, 3H), 1.20 (s, 9H) ppm; ESI mass spectrum m/z (rel. int.) 460 (M+Na, 100), 438 (M+H, 20). Subjecting the nitrile obtained above to the Pinner amidine reaction protocol as illustrated for Example 10 afforded the desired product in 5% yield as colorless crystals following preparative HPLC (reverse phase, acetonitrile:water) purification. ¹ HNMR(DMSO-d₆) δ: 10.8 (s, 1H), 9.41 (bs, 1.5H), 9.20 (bs, 1.5H), 7.97 (s, 1H), 7.84-7.77 (m, 9H), 7.47 (s, 1H), 7.08 (s, 1H), 3.73 (s, 1H), 2.35 (s, 3H) ppm; ESI mass spectrum m/z (rel. int.) 455 (M+H, 100). The de-tertbutylated sulfonamide was obtained in 30% yield (colorless crystals); ¹ HNMR(DMSO-d₆) δ: 10.85 (s, 1H), 9.40 (bs, 4), 7.95 (s, 1H), 7.89-7.66 (m, 7H), 7.07 (s, 1H), 2.34 (s, 3H) ppm; ESI mass spectrum 381.3.

EXAMPLE 58 1-(3-amidino)phenyl-3-methyl-5-[(4'-trifluoromethylphenyl)-aminocarbonyl]pyrazole

Coupling of 4-amino-1-trifluoromethylbenzene with the acid chloride obtained in Example 10 afforded the desired benzonitrile precursor in 80% yield. ¹ HNMR(CDCl₃) δ: 8.17 (s, 1H), 7.79 (s, 1H), 7.75-7.50 (m, 7H), 6.73 (s, 1H), 2.39 (s, 3H) ppm; Ammonia CI mass spectrum 388 (M+NH₄, 34), 371 (M+H, 100). Subjecting the nitrile obtained above to the Pinner amidine reaction protocol as illustrated for Example 10 afforded the desired product in 60% yield as colorless crystals following preparative HPLC (reverse phase, acetonitrile:water) purification. ¹ HNMR(DMSO-d₆) δ: 9.40 (bs, 1.5H), 9.20 (bs, 1.5H), 8.09 (s, 1H), 7.90 (s, 1H), 7.83-7.75 (dd, J=7.6 & 8.4 Hz), 7.68-7.53 (m, 4H), 6.97 (s, 1H), 2.29 (s, 2H) ppm; ESI mass spectrum m/z (rel. int.) 388.1 (M+H, 100); HRMS calcd for C₁₉ H₁₇ N₅ F₃ O 388.138520, Found 388.139013.

EXAMPLE 59 1-(3-amaidino)phenyl-3-methyl-5-[(4'-benzylsulfonylpiperidyl)-aminocarbonyl]pyrazole

Coupling of 4-amino-1-benzylsulfonylpiperidine with the acid chloride obtained in Example 10 afforded the desired coupled product which when subjected to the Pinner amidine reaction protocol as illustrated for Example 10 afforded the desired product in 15% yield as colorless crystals following preparative HPLC (reverse phase, acetonitrile:water) purification. ¹ HNMR(DMSO-d₆) δ: 9.40 (bs, 1.5H), 9.60 (bs, 1.5H), 8.59 (d, J=8 Hz, 1H), 7.86 (s, 1H), 7.77 (m, 1H), 7.75 (m, 3H), 7.38 (m, 5H), 6.79 (s, 1H), 4.40 (s, 2H), 3.50 (bd, 2H), 2.73 (m, 2H), 1.74 (m, 2H), 1.50 (m, 2H), 2.28 (s, 3H) ppm; ESI mass spectrum m/z (rel. int.) 481 (M+H, 100); HRMS calcd. for C₂₄ H₂₉ N₆ 481.202186. Found 481.201227.

EXAMPLE 60 1-(3-amidinophenyl)-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)-N-methylaminocarbonyl]-3-methylpyrazole, Trifluoroacetic Acid Salt

Part A. Synthesis of 1-(3-cyanophenyl)-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)-N-methylaminocarbonyl]-3-methylpyrazole

Standard coupling of 1-(3-cyanophenyl)-3-methyl-pyrazol-5-yl carboxylic acid and 2-tert-butylsulfonamide-1-biphenyl-N-methyl aniline afforded a yellow foam (67%), ¹ HNMR(CDCl₃)δ: 8.16 (d, j=7.69 Hz, 1H), 7.63 (m, 6H), 7.33 (m, 3H), 6.83 (brd m, 2H), 6.23 (s, 1H), 3.43 (s and m, 4H), 2.27 (s, 3H), 1.02 (s, 9H); MS (ESI) m/z 528.4 (M+H)⁺, 550.4 (M+Na)⁺.

Part B:

The Pinner amidine reaction protocol as illustrated for Example 10 afforded the desired product. ¹ HNMR(DMSO-d₆)δ: 9.45 (s, 1.5H), 9.12 (s, 1.5H), 8.16 (d, j=7.69 Hz, 1H), 7.81 (m, 7H), 7.30 (m, 5H), 7.15 (m, 2H), 3.10 (s, 3H), 2.12 (s, 3H) ppm; HRMS 489.170886 (calcd); 489.170289 (obs.); Analysis calcd for C₂₅ H₂₄ N₆ O₃ S (TFA) 1.1 (H₂ O) 0.3 C:52.74, H:4.18, N:13.57; found C:52.67, H:4.28, N:13.57.

EXAMPLE 61 1-(3-amidinophenyl)-5-[(4'-fluoro-[1,1']-biphen-4-yl)-aminocarbonyl]-3-methylpyrazole, Trifluoroacatic Acid Salt

Part A. Preparation of 2-tert-butylsulfonamide-4-fluoro-1-biphenyl trifluoroacetamide

Standard Suzuki coupling between 1-bromo-2-tert-butylsulfonamide-4-fluorobenzene (J. Indian Chem. Soc. Vol. 38, No.2, 1961,117) and 4-trifluoracetamide-1-phenyl boronic acid afforded a solid (57%). ¹ HNMR(CDCl₃)δ: 8.11 (dd, j=2.19, 6.59 Hz, 1H), 8.03 (s, 1H), 7.76 (m, 1H), 7.70 (d, j=8.79 Hz, 2H), 7.61 (d, j=8.79 Hz, 2H), 7.30 (m, 1H), 4.78 (s, 1H), 1.27 (s, 9H) ppm; MS (DCI) m/z 436 (M+NH₄)⁺ ; Analysis calcd for C₁₈ H₁₈ F₄ N₂ O₃ S₁ C:51.67, H:4.34, N:6.70, found C:51.66, H:4.26, N:6.65.

Part B. Preparation of 2-tert-butylsulfonamide-4-fluoro-1-biphenyl aniline

To the compound from part A (0.93 g, 2.2 mmol) in methanol was added 0.5 M LiOH (8 mL, 4 mmol)and heated to reflux 2h. The reaction was cooled and concentrated. The aqueous residue was extracted with CH₂ Cl₂. The combined organic layers were washed with water, brine and dried (MgSO₄) to afford 0.7 g (98%) solid; mp=158-160° C., ¹ HNMR(CDCl₃)δ: 8.07 (dd, j=2.2, 6.96 Hz, 1H), 7.66 (m, 1H), 7.40 (d, j=8.43 Hz, 2H), 4.75 (s, 1H), 3.80 (s, 2H), 1.25 (s, 9H) ppm, MS (DCI) m/z 340 (M+NH₄)⁺.

Part C:

Standard coupling of 1-(3-cyanophenyl)-3-methyl-pyrazol-5-yl carboxylic acid and 2-tert-butylsulfonamide-4-fluoro-1-biphenyl aniline afforded a 85% yield of impure nitrile that was carried on to the next step. MS (DCI) m/z 531 (M+H)⁺, 549 (M+NH₄)⁺.

Part D:

The nitrile from part C was subjected to the standard Pinner conditions to give the title amidine, ¹ HNMR(DMSO-d₆)δ: 10.7 (s, 1H), 9.43 (s, 1.5H), 9.01 (s, 1.5H), 7.99 (m, 3H), 7.81 (d, j=7.69 Hz, 2H), 7.81 (m, 5H), 7.68 (d, j=8.79 Hz, 2H), 7.55 (t, j=8.79 Hz, 1H), 7.06 (s, 1H), 2.27 (s, 3H); HRMS 493.145814 (calcd); 493.145228 (obs.).

EXAMPLE 62 1-(3-amidinophenyl)-5-[[5-(2'-aminosulfonylphenyl)pyridin-2-yl]aminocarbonyl]-3-methylpyrazole, Trifluoroacetic Acid Salt

Part A. Synthesis of 1-(3-cyanophenyl)-5-[[5-(2'-t-butylaminosulfonylphenyl)pyridin-2-yl]aminocarbonyl]-3-methylpyrazole

Standard coupling of 1-(3-cyanophenyl)-3-methyl-pyrazol-5-yl carboxylic acid and 2-t-butylsulfonamide-1-pyridyl phenyl aniline afforded the title compound (44%), ¹ HNMR(CDCl₃)δ: 8.59 (s, 1H), 8.37 (m, 1H), 8.23 (t, j=8.42, 2H), 7.94 (m, 7H), 6.77 (s, 1H), 3.94 (s, 1H), 2.41 (s, 3H), 1.10 (s, 9H) ppm, MS (ESI) 515.4 (M+H)⁺.

Part B: The above compound was subjected to standard Pinner reaction and HPLC purification (35%) ¹ HNMR(DMSO-d₆)δ: 11.21 (s, 1H), 9.44 (s, 1.5H), 9.23 (s, 1.5H), 8.37 (t, j=1.47 Hz, 1H), 8.07 (dd, j=7.30, 1.47 Hz, 1H), 7.99 (d, j=7.69 Hz, 2H), 7.85 (m, 1H), 7.79 (dd, j=9.52, 2.20 Hz, 2H), 7.73 (d, j=7.69 Hz, 1H), 7.69 (m, 2H), 7.44 (s, 2H), 7.40 (dd, j=2.20, 7.69 Hz, 1H), 7.18 (s, 1H), 2.33 (s, 3H) ppm; HRMS 476.150485 (calcd), 476.149493 (observed); Analysis calcd for C₂₃ H₂₁ N₇ O₃ S(TFA)1.9 C:46.51, H:3.33, N:14.17, found C;46.60, H:3.51, N:14.17.

EXAMPLE 63 1-(3-cyanophenyl)-5-[[5-(2'-aminosulfonylphenyl) pyridin-2-yl]aminocarbonyl]-3-methylpyrazole, Trifluoroacetic Acid Salt

1-(3-cyanophenyl)-5-[[5-(2'-t-butylaminosulfonylphenyl)pyridin-2-yl]aminocarbonyl]-3-methylpyrazole (0.18 g, 0.28 mmol) was heated to reflux in trifluoracetic acid (6 mL) for 15 minutes. The reaction was concentrated and the residue purified by HPLC to afford 69 mg (43%) of the title compound. ¹ HNMR(DMSO-d₆)δ: 11.15 (s, 1H), 8.37 (d, j=2.20 Hz, 1H), 8.07 (m, 3H), 7.89 (d, j=7.69 Hz, 1H), 7.82 (m, 2H), 7.70 (d, j=8.05 Hz, 1H), 7.67 (m, 2H), 7.42 (s, 1H), 7.40 (dd, j=1.83, 6.96 Hz, 2H), 7.18 (s, 1H), 2.32 (s, 3H) ppm; HRMS 459.123936 (calcd), 459.122035 (obs.); Analysis calcd for C₂₃ H₁₈ N₆ O₃ S₁ (TFA)0.6: C:55.16, H:3.56, N:15.95, found C:54.89, H:3.69, N:15.67.

EXAMPLE 64 1-(3-amidinophenyl)-5-[(2'-trifluoromethyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-methylpyrazole, Trifluoroacetic Acid Salt

Part A: 2-Trifluoromethylbromobenzene and 4-trifluoroacetamide phenylboronic acid were combined in standard Suzuki reaction to afford a 28% yield of 2-trifluoromethyl-1-biphenyl trifluoroacetamide, after purification by flash chromatography on silica gel using hexanes/ethyl acetate (6:1) as eluent. ¹ HNMR(CDCl₃)δ: 7.90 (s, 1H), 7.77 (d, j=7.69 Hz, 1H), 7.64 (d, j=8.43 Hz, 2H), 7.58 (d, j=6.59 Hz, 1H). 7.51 (m, 1H), 7.39 (d, j=8.42 Hz, 2H), 7.33 (m, 1H) ppm, MS (ESI) m/z 334 (M+H)+. 2-trifluoromethyl-1-biphenyl trifluoroacetamide was hydrolyzed with base as described above to give the free aniline (90%) which was used in next step without purification. MS (DCI) m/z 238.1 (M+H)⁺, 255.1 (M+NH₄)⁺.

Part B. Preparation of 1-(3-cyanophenyl)-5-[(2'-trifluoromethyl-[1,1']-biphen-4-yl)-aminocarbonyl]-3-methyl pyrazole

Standard coupling of 1-(3-cyanophenyl)-3-methyl-pyrazol-5-yl carboxylic acid and 2-trifluoromethyl-1-biphenyl aniline afforded a yellow foam (50%) which was used in the next step without purification. MS (ESI) m/z 447.3 (M+H)⁺.

Part C: The nitrile from part B was subjected to standard Pinner conditions, purified via HPLC and freeze-dried to yield the title compound (32%). ¹ HNMR(DMSO-d₆)δ: 10.68 (s, 1H), 9.44 (s, 1.5H), 9.10 (s, 1.5H), 7.97 (s, 1H), 7.84 (d, j=7.7 Hz, 2H), 7.76 (m, 5H), 7.67 (m, 1H), 7.40 (d, j=7.33 Hz, 1H), 7.31 (d, j=8.40 Hz, d), 7.04 (s, 1H), 2.35 (s, 3H) ppm, HRMS: 464.169820 (calcd), 464.171171 (obs.); Analysis calcd for C₂₅ H₂₀ F₃ N₅ O (TFA) C:56.16, H:3.67, N:12.13, found C:55.77, H:3.79, N:11.85.

EXAMPLE 65 1-(3-aminocarbonylphenyl)-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-methylpyrazole

To 1-(3-cyanophenyl)-5-[(2'-t-butylaminosulfonyl-[1,1']-biphen-4-yl-aminocarbonyl]-3-methyl pyrazole (0.18 g, 0.36 mmol) was added concentrated sulfuric acid (5 mL) and reaction stirred for 48h. Ice and water were added a solid precipitated. The mixture was extracted with ethyl acetate, washed with sat'd sodium bicarbonate and dried (MgSO₄). Purification by flash chromatography on silica gel using 1-10% methanol in methylene chloride as eluent afforded 88 mg (52%) of the title compound, ¹ HNMR(DMSO-d₆)δ: 10.63 (s, 1H), 8.12 (s, 1H), 8.04 (m, 2H), 7.90 (m, 1H), 7.69 (d, j=8.42 Hz, 2H), 7.62 (m, 5H), 7.36 (d, j=8.42 Hz, 2H), 7.32 (m, 1H), 7.24 (s, 2H), 6.93 (s, 1H), 2.50 (s, 3H) ppm, HRMS 476.139251 (calcd), 476.139200 (observed).

EXAMPLE 66 1-(3-amidinophenyl)-5-[(2'-aminosulfonyl)-3-chloro-[1,1']-biphen-4-yl)aminocarbonyl]-3-methylpyrazole

Part A: 1-(3-cyanophenyl)-3-methyl-pyrazol-5-yl carboxylic acid and 4-bromo-2-chloroaniline were coupled via standard conditions (67%). ¹ HNMR(CDCl₃)δ: 8.27 (d, j=8.79 Hz, 1H), 8.17 (s, 1H), 7.82 (t, j=1.80 Hz, 1H), 7.75 (m, 2H)7.59 (m, 2H), 7.42 (dd, j=8.78, 2.2 Hz, 1H), 6.72 (s, 1H), 2.41 (s, 3H) ppm.

Part B: The bromo compound from part A (0.4 g, 0.96 mmol), 2-t-butylsulfonamide phenylboronic acid (0.32 g, 1.2 mmol), 2M sodium carbonate (1 mL), and 1:1 toluene/ethanol were combined and degassed with nitrogen. Tetrakistriphenyphosphine palladium(0) (1 mg) was added and the reaction refluxed for 18h. The reaction was filtered, concentrated and extracted with ethyl acetate and dried(MgSO₄). Purification by flash chromatography on silica gel using 1:1 hexanes/ethyl acetate as eluent afforded 0.43 g (81%). ¹ HNMR(CDCl₃)δ: 8.45 (d, j=8.42 Hz, 1H), 8.32 (s, 1H), 8.18 (dd, j=1.47, 7.69 Hz, 1H), 7.85 (d, j=1.83 Hz, 1H), 7.79 (d. j=8.05 Hz, 1H), 7.72 (d, j=7.69 Hz, 1H), 7.61 (m, 4H), 7.39 (dd, j=2.20, 8.79 Hz, 1H), 7.28 (m, 1H), 6.76 (s, 1H), 3.67 (s, 1H), 2.43 (s, 3H), 1.07 (s, 9H) ppm., MS (ESI) m/z 548.3 (M+H)⁺, 570.3 (M+Na)⁺.

Part C: The nitrile from part B was subjected to the standard Pinner conditions to afford the amidine (43%). ¹ HNMR(DMSO-d₆)δ: 10.36 (s, 1H), 9.43 (s, 1.5H), 9.09 (s, 1.5H), 8.05 (dd, j=6.96, 2.20 Hz, 1H), 7.96 (s, 1H), 7.82 (d, j=7.32 Hz, 2H), 7.71 (m, 1H), 7.65 (m, 2H), 7.57 (d, j=6.59 Hz, 1H), 7.54 (s, 1H), 7.46 (s, 2H), 7.39 (m, 2H), 7.06 (s, 1H), 2.35 (s, 3H) ppm, HRMS 509.116263 (calcd), 509.117360 (observed); Analysis calcd for C₂₄ H₂₁ ClN₆ O₃ S₁ (TFA) (H₂ O) C:48.72, H:3.77, N:13.11, found C:48.56, H:3.53, N:12.75.

EXAMPLE 67 1-(3-amidinophenyl)-5-[(2'-trifluoromethyl)-3-chloro-[1,1']-biphen-4-yl) aminocarbonyl]-3-muethylpyrazol, Trifluoroacetic Acid Salt

Part A: N-(2-chloro-4-bromophenyl)-1-(3-cyanophenyl)-3-methylpyrazole carboxamide (0.4 g, 0.96 mmol), 2-trifluoromethylphenylboronic acid (0.24 g, 1.2 mmol), 1M sodium carbonate (1 mL) in 1:1 toluene/ethanol (10 mL) were degassed with nitrogen. Tetrakistriphenyphosphine palladium(0) (1 mg) was added and the reaction refluxed for 18h. The reaction was filtered, concentrated and extracted with ethyl acetate and dried (MgSO₄). Purification by flash chromatography on silica gel using 1:1 hexanes/ethyl acetate as eluent afforded 0.41 g (90%). ¹ HNMR(CDCl₃)δ: 8.40 (d, j=8.42 Hz, 1H), 8.29 (s, 1H), 7.85 (d, j=1.83 Hz, 1H), 7.77 (d, j=8.05 Hz, 2H), 7.71 (d, j=7.60 Hz, 1H), 7.60 (t, j=8.05 Hz, 2H), 7.52 (t, j=7.69 Hz, 1H), 7.42 (d, j=1.84 Hz, 1H), 7.29 (m, 1H), 6.75 (s, 1H), 4.11 (s, 1H), 2.42 (s, 3H) ppm, MS (ESI) m/z 481.2 (M+H)⁺, 503 (M+Na)⁺.

Part B: The nitrile from part A was subjected to the standard Pinner conditions to afford the amidine (36%). ¹ HNMR (DMSO-d₆) δ: 10.4 (s, 1H), 9.43 (s, 1.5H), 9.13 (s, 1.5H), 7.96 (d, j=1.83, 1H), 7.87 (m, 3H), 7.76 (m, 3H), 7.62 (d, j=8.06 Hz, 1H), 7.52 (d, j=1.83 Hz, 1H), 7.47 (d, j=7.69 Hz, 1H), 7.34 (dd, j=8.42, 1.83 Hz, 1H), 7.07 (s, 1H), 2.35 (s, 3H) ppm, HRMS 498.130848 (calcd), 498.128257 (observed); Analysis for C₂₅ H₁₉ ClF₃ N₅ O (TFA) calcd C:53.00, H:3.29, N:11.44, found C:53.33, H:3.36, N:11.55.

EXAMPLE 68 1-(3-amidinophenyl)-5-[(2'-aminosulfonyl-[1,1']-biphien-4-yl) aminocarbonyl]-3-n-butylpyrazole, Trifluoroacetic Acid Salt

Part A. Synthesis of ethyl 1-(3-cyanophenyl)-3-n-butyl-pyrazol-5-yl carboxylate

Ethyl 2-methoxyimino-4-oxooctanoate (W. T. Aston, et al, J. Het. Chem., 30 (1993)2, 307) (0.69 g, 3.0 mmol) and 3-cyanophenyl hydrazine hydrochloride (0.66 g, 3.9 mmol) were combined in acetic acid (15 mL) and heated to reflux for 18h. The reaction was concentrated and the residue was partioned between ethyl acetate and 1N HCl. The organic layer was washed with water and dried (MgSO₄). A mixture of regioisomers (ca.9:1) was obtained and separated by flash chromatography on silica gel using 4:1 hexanes/ethyl acetate as eluent affording 0.56 g (63%) of the desired isomer as a yellow oil. ¹ HNMR (CDCl₃) δ: 7.77 (d, j=1.83 Hz, 1H), 7.70 (d, j=7.69, 1.83 Hz, 2H), 7.58 (t, j=7.69 Hz, 1H), 6.88 (s, 1H), 4.30 (q, j=6.96 Hz, 2H), 2.72 (t, j=7.69 Hz, 2H), 1.71 (m, 2H), 1.45 (m, 2H), 1.32 (t, j=6.96 Hz, 3H), 0.98 (t, j=7.33 Hz, 3H) ppm; MS (DCI) m/z 298 (M+H)⁺.

Part B. Preparation of 1-(3-cyanophenyl)-3-n-butyl-pyrazol-5-yl carboxylic acid

The ester from part A. (0.96 g, 3.2 mmol) was hydrolized with 1N NaOH (5 mL) in THF/water (5 mL) for 18h. Acid-base workup afforded 0.8 g (92%) acid. ¹ HNMR(CDCl₃)δ: 7.79 (d, j=1.83 Hz, 1H), 7.75 (dd, j=1.l, 8.05 Hz, 1H), 7.66 (d, j=7.69 Hz, 1H), 7.56 (t, j=7.69 Hz, 1H), 6.88 (s, 1H), 2.71 (t, j=7.32 Hz, 2H), 1.70 (m, 2H), 1.45 (m, 2H), 0.97 (t, j=7.32 Hz, 3H) ppm; MS (DCI) m/z 270 (M+H)⁺.

Part C: Preparation of 1-(3-cyanophenyl)-5-[(2'-t-butylaminosulfonyl-[1,1']-biphen-4-yl) aminocarbonyl]-3-N-butylpyrazole

Standard coupling of ethyl 1-(3-cyanophenyl)-3-n-butyl-pyrazol-5-yl carboxylate 2-t-butylsulfonamide-1-biphenyl aniline afforded a yellow solid (73%), ¹ HNMR(CDCl₃)δ: 8.17 (dd, j=1.1, 7.69 Hz, 1H), 8.03 (s, 1H), 7.82 (s, 1H), 7.77 (d, j=8.06, 1H), 7.68 (s+d, j=7.69 Hz, 3H), 7.55 (m, 5H), 7.31 (dd, j=1.4, 7.7 Hz, 1H), 6.76 (s, 1H), 3.64 (s.1H), 2.77 (t, j=7.69 Hz, 2H), 1.75 (m, 2H), 1.44 (mn, 2H), 1.03 (s, 9H), 1.00 (t, j=7.69 Hz, 3H) ppm.

Part D: The nitrile from part A. was subjected to standard Pinner conditions to afford the title amidine (57%). ¹ HNMR(DMSO-d₆)δ: 10.65 (s, 1H), 9.44 (s, 1.5H), 9.08 (s, 1.5H), 7.83 (m, 3H), 7.70 (d, j=9.15 Hz, 2H)7.64 (m, 2H), 7.37 (d, j=8.42 Hz, 2H), 7.32 (d, j=7.32 Hz, 1H), 7.28 (s, 2H), 7.06 (s, 1H), 2.72 (t, j=7.69 Hz, 2H), 1.71 (m, 2H), 1.43 (m, 2H), 0.97 (t, j=7.33 Hz, 3H) ppm, HRMS 517.202186 (calcd), 517.201333 (obs.); Analysis calcd for C₂₇ H₂₈ N₆ O₃ S(TFA)((H₂ O)0.8, C:54.00, H:4.78, N:3.03;found C:54.23, H:4.46, N:12.80.

EXAMPLE 69 1-(3-amidinophenyl)-5-[(2'-trifluoromethyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-N-butylpyrazole, Trifluoroacetic Acid Salt

Part A: Preparation of 1-(3-cyanophenyl)-5-[(2'-trifluoromethyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-N-butyl pyrazole.

Standard coupling of ethyl 1-(3-cyanophenyl)-3-n-butyl-pyrazol-5-yl carboxylate and 2-trifluoromethyl-1-biphenyl aniline afforded the nitrile. ¹ HNMR(CDCl₃)δ: 7.86 (s, 1H), 7.74 (m, 3H), 7.66 (m, 2H), 7.56 (m, 4H), 7.33 (m, 3H), 6.69 (s, 1H), 2.76 (t, j=7.96 Hz, 2H), 1.75 (m, 2H), 1.44 (m, 2H), 0.98 (t, j=7.32 Hz, 3H) ppm; MS (ESI) m/z 489 (M+H)⁺.

Part B: 1-(3-amidinophenyl)-5-[(2'-trifluoromethyl-[1,1']-biphen-4-yl) aminocarbonyl]-3-N-butyl pyrazole was prepared from the nitrile from part A by standard Pinner conditions. ¹ HNMR(DMSO-d₆)δ: 10.00 (s, 1H), 9.43 (s, 1.5H), 9.02 (s, 1.5H), 7.96 (s, 1H), 7.84-7.70 (m, 7H), 7.63 (t, j=7.69 Hz, 1H), 7.40 (d, j=7.33 Hz, 1H), 7.31 (d, j=8.42 Hz, 2H), 7.08 (s, 1H), 2.72 (t, j=7.33 Hz, 2H), 1.73 (m, 2H), 1.45 (m, 2H), 0.97 (t, j=7.33 Hz, 3H) ppm; HRMS 506.216771 (calcd.), 506.214378 (obs.); Analysis for C₂₈ H₂₆ F₃ N₅ O(TFA) (H₂ O)0.8: C:56.84, H:4.55, N:11.05, found C:56.99, H:4.41, N:10.99.

EXAMPLE 70 1-(3-amidinophenyl)-5-[[5-(2'-aminosulfonylphenyl)pyridin-2-yl]aminocarbonyl]-3-n-butylpyrazole, Trifluoroacetic Acid Salt

Part A: Preparation of 1-(3-cyanophenyl)-5-[[5-(2'-tert-butylsulfonaminocarbonylphenyl)pyridin-2-yl]-aminocarbonyl]-3-n-butylpyrazole

Standard coupling of 1-(3-cyanophenyl)-3-n-butyl-pyrazol-5-yl carboxylic acid and 5-(2'-tert-butylsulfonaminocarbonylphenyl)pyridin-2-yl amine afforded the nitrile (25%). ¹ HNMR(CDCl₃)δ: 8.59 (1H, s), 8.37 (d, j=2.20 Hz, 1H), 8.24 (m, 2H), 7.85 (m, 2H), 7.78 (m, 1H), 7.76 (m, 1H), 7.70 (m, 3H), 7.30 (dd, j=1.47, 9.15 Hz, 1H), 6.79 (s, 1H), 3.95 (s, 1H), 2.76 (t, j=7.33 Hz, 2H), 1.73 (m, 2H), 1.47 (m.2H), 1.10 (s, 9H), 0.98 (t, j=7.33 Hz, 3H) ppm; MS (ESI) m/z 557.29 (M+H)⁺, 579.27 (M+NH₄)⁺.

Part B: 1-(3-amidinophenyl)-5-[[5-(2'-aminosulfonylphenyl)pyridin-2-yl]aminocarbonyl]-3-n-butyl pyrazole, trifluoroacetic acid salt was prepared (51%) from the nitrile in part A by standard Pinner conditions. ¹ HNMR(DMSO-d₆)δ: 11.21 (s, 1H), 9.43 (s, 1.5H), 9.04 (s, 1.5H), 8.37 (d, j=2.20 Hz, 1H), 8.07 (dd, j=1.83, 7.32 Hz, 1H), 8.02 (d, j=8.79 Hz, 1H), 7.96 (s, 1H), 7.84 (m, 3H), 7.73 (d, j=7.69 Hz, 1H), 7.86 (m, 2H), 7.44 (s, 2H), 7.40 (dd, j=1.83, 6.96 Hz, 1H), 7.24 (s, 1H), 2.70 (t, j=7.32 Hz, 2H), 1.69 (m, 2H), 1.45 (m, 2H), 0.97 (t, j=7.32 Hz, 3H) ppm; HRMS 518.197435 (calcd), 518.195873 (obs.); Analysis calc'd for C₂₆ H₂₇ N₇ O₃ S(TFA)1.5: C:50.58, H:4.17, N:14.24, found C:50.76, H:4.12, N:14.26.

EXAMPLE 71 1-(3-amidinophenyl)-5-[(2'-trifluoromethyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-trifluoromethyl-4-methoxypyrazole, Trifluoroacetic Acid Salt

Part A: 1-(3-cyanophenyl)-3-trifluoromethyl-4-methoxy-5-[(2'-trifluoromethyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole, ¹ HNMR(CDCl₃)δ: 8.97 (s, 1H), 7.80 (t, j=1.83 Hz, 1H), 7.76 (s+m, 3H), 7.61 (d+m, j=8.70 Hz, 4H), 7.50 (t, j=7.32 Hz, 1H), 7.34 (d+m, j=8.70 Hz, 3H), 4.17 (s, 3H) ppm; MS (DCI) m/z 531.2 (M+H)⁺.

Part B: 1-(3-amidinophenyl)-5-[(2'-trifluoromethyl-[1,1']-biphen-4-yl) aminocarbonyl]-3-trifluoromethyl-4-methoxypyrazole, trifluoroacetic acid salt was prepared from the nitrile of part A by standard Pinner conditions. ¹ HNMR(DMSO-d₆)δ: 11.06 (s, 1H), 9.47 (s, 1.5H), 9.15 (s, 1.5H), 8.03 (s, 1H), 7.92 (m, 4H), 7.75 (m, 1H), 7.70 (m, 3H), 7.40 (d, j=7.33 Hz, 1H), 7.33 (d, j=8.42 Hz, 2H), 3.96 (s, 3H) ppm; HRMS 548.152120 (calcd), 548.150458 (obs.); Analysis calcd for C₂₆ H₁₉ F₆ N₅ O₂ (TFA)1.3 (H₂ O)0.5: C:48.75, H:3.05, N:9.94, found C:49.04, H:2.70, N:9.85.

EXAMPLE 72 1-(3-amidinophenyl)-5-[(2'-trifluoromethyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-trifluoromethylpyrazole, Trifluoroacetic Acid Salt

Part A: Preparation of 1-(3-cyanophenyl)-3-trifluoromethyl-5-(4-bromobenzene) aminocarbonyl)pyrazole

Standard coupling of 1-(3-cyanophenyl)-3-trifluoromethylpyrazole-5-yl carboxylic acid and 4-bromoaniline afforded the title compound in 77% yield ms (DCI) m/z 452-454 (M+H)⁺.

Part B: Preparation of 1-(3-cyanophenyl)-3-trifluoromethyl-5-[(2'-trifluoromethyl-[1,1']-biphen-4-yl) aminocarbonyl]pyrazole

Standard Suzuki coupling of the bromo compound from Part A and 2-trifluoromethyl phenyl boronic acid afforded the title compound (80.7%). ¹ HNMR(CDC₃)δ: 7.88 (m, 5H), 7.65 (d, j=8.06 Hz, 1H), 7.59 (m, 4H), 7.35 (d, j=8.79 Hz, 2H), 7.29 (s, 1H), 7.15 (s, 1H) ppm; MS (ESI) m/z 501.2 (M+H)⁺.

Part C: 1-(3-amidinophenyl)-5-[(2'-trifluoromethyl-[1,1']-biphen-4-yl) aminocarbonyl]-3-trifluoromethyl-pyrazole, trifluoroacetic acid salt was prepared from the nitrile in part B by standard Pinner conditions. ¹ HNMR(DMSO-d₆)δ: 10.86 (s, 1H), 9.46 (s, 1.5H), 9.11 (s, 1.5H), 8.05 (s, 1H), 7.95 (d, j=8.06 Hz, 2H), 7.84 (d, j=9.16 Hz, 1H), 7.78 (m, 3H), 7.73 (d, j=8.43 Hz, 2H), 7.63 (m, 1H), 7.40 (d, j=7.69 Hz, 1H), 7.32 (d, j=8.43 Hz, 2H) ppm; HRMS 518.141555 (calcd), 518.141456 (obs.); Analysis calcd for C₂₅ H₁₇ F₆ N₅ O(TFA)1.1: C:50.82, H:2.84, N:10.89, found C:50.57, H:2.96, N:10.75.

EXAMPLE 73 1-(3-amidinophenyl)-5-[(2'-sulfonylmethyl-[1,1']-biphen-4-yl) aminocarbonyl]-3-trifluoromethyl-pyrazole, Trifluoroacetic Acid Salt

Part A: 1-(3-cyanophenyl)-5-[(2'-sulfonylmethyl-[1,1']-biphen-4-yl) aminocarbonyl]-3-trifluoromethyl-pyrazole

Standard coupling of 1-(3-cyanophenyl)-3-trifluoromethylphenyl and 2-sulfonylmethyl-1-biphenyl aniline afforded the nitrile in 65% yield. ¹ HNMR(CDCl₃)δ: 9.81 (s, 1H), 8.24 (d, j=8.06 Hz, 1H), 7.86 (d, j=1.83 Hz, 1H), 7.82 (m, 4H), 7.66 (m, 3H), 7.46 (s, 1H), 7.44 (d, j=6.23 Hz, 2H), 7.37 (dd, j=7.30, 1.46 Hz, 1H), 2.68 (s, 3H) ppm; MS (ESI) 533.11 (M+Na)⁺.

Part B: The title compound was prepared from the nitrile in part A by standard Pinner conditions, ¹ HNMR(DMSO-d₆) δ: 10.92 (s, 1H), 9.47 (s, 1.5H), 9.27 (s, 1.5H), 8.11 (dd, j=7.69, 1.1 Hz, 1H), 8.06 (s, 1H), 7.97 (m, 2H), 7.79 (m, 6H), 7.41 (s+m, 2H), 2.85 (s, 3H) ppm; HRMS 528.131721 (calcd), 528.1331 (obs.); Analysis calcd for C₂₅ H₂₀ F₃ N₅ O₃ S(TFA) (H2O)0.6: C:49.71, H:3.43, N:10.74, found C:49.48, H:3.35, N:10.97.

EXAMPLE 74 1-(3-amidinophenyl)-5-[(2'-aminosulfonyl-3-bromo-[1,1']-biphen-4-yl)aminocarbonyl]-3-methyl-pyrazole, Trifluoroacetic Acid Salt

Part A: Synthesis of 1-(3-cyano)phenyl-3-methyl-5-[(2'-t-butylaminosulfonyl-3-bromo-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole

The title compound was obtained by standard acid chloride coupling, of 1-(3-cyanophenyl)-3-methyl-pyrazole acid and 4-amino-2'-t-butylaminosulfonyl-3-bromo-[1,1']-biphen-4-yl (71%). ¹ HNMR(CDCl₃) δ: 8.44 (d, j=8.79 Hz, 1H), 8.34 (s, 1H), 8.18 (dd, j=1.47, 7.69 Hz, 1H), 7.84 (m, 1H), 7.75 (d, j=1.83 Hz, 1H), 7.69 (m, 1H), 7.61 (m, 3H), 7.43 (dd, j=1.83, 8.43 Hz, 1H), 7.28 (m, 1H), 6.77 (s, 1H), 3.66 (s, 1H), 2.43 (s, 3H), 1.08 (s, 9H) ppm; MS (ESI) 614-616 (M+Na)⁺.

Part B: The title compound was prepared from the nitrile in part A by standard Pinner conditions. ¹ HNMR(DMSO-d₆) δ: ¹ HNMR(DMSO-d₆)δ: 10.35 (s, 1H), 9.43 (s, 1.5H), 9.08 (s, 1.5H), 8.05 (m, 1H), 7.97 (s, 1H), 7.81 (m, 2H), 7.74 (d, j=7.69, 1H), 7.70 (d, j=1.83 Hz, 1H), 7.65 (m, 2H), 7.53 (d, j=8.05 Hz, 1H), 7.46 (m, 3H), 7.37 (m, 1H), 7.05 (s, 1H), 2.35 (s, 3H); HRMS 553.065747 (calcd), 553.066135 (obs.); Analysis calcd for C₂₄ H₂₁ BrN₆ O₃ S(TFA)(H2O)0.5: C:46.16, H:3.43, N:12.42, found C:46.06, H:3.15, N:12.14.

EXAMPLE 75 1-(3-aminocarbonylphenyl)-5-[(2'-aminosulfonyl-3-bromo-[1,1']-biphen-4-yl)aminocarbonyl]-3-methyl Pyrazole, Trifluoroacetic Acid Salt

To 1-(3-cyano)phenyl-3-trifluoromethyl-5-[(2'-t-butylaminosulfonyl-3-bromo-[1,1']-biphen-4-yl) aminocarbonyl]-pyrazole (Part A Example 74) (82 mg, 0.14 mmol), cooled to 0° C. was added conc. sulfuric acid (5 mL). The reaction was allowed to warm to room temperature and was stirred 18h. Water was added and the reaction was extracted with methylene chloride. Purification by HPLC afforded 35 mg (46%) of the title amide, ¹ HNMR(DMSO-d₆)δ: 10.27 (s, 1H), 8.11 (s, 1H), 8.05 (m, 2H), 7.90 (d, j=7.32 Hz, 1H), 7.68 (d, j=1.84 Hz, 1H), 7.64 (m, 3H), 7.56 (dd, j=8.4, 2.2 Hz, 2H), 7.51 (s, 1H), 7.44 (m, 3H), 7.36 (m, 1H), 6.96 (s, 1H), 2.34 (s, 3H) ppm; HRMS 554.049762 (calcd), 554.051045 (obs.).

EXAMPLE 76 1-(3-amidinophenyl)-3-methyl-5-[(2'-aminosulfonyl)-[1,1']-biphen-4-yl)methylcarbonyl]pyrazole, Trifluoroacetic Acid Salt

Part A: Preparation of 1-[(3-cyanophenyl)-5-(4-bromophenyl)acetyl]-3-methylpyrazole

To zinc dust (0.56 g, 8.6 mmol) in THF (10 mL) was added 5 drops of 1,2-dibromoethane. The mixture was heated to reflux for 5 minutes, then cooled to 0° C. and 4-bromobenzylbromide (1.85 g, 7.4 mmol) in THF (15 mL) was added dropwise. The reaction was stirred at 0° C. for 2h, then it was cannulated into a suspension of LiCl (0.6 g, 1.4 mmol), CuCN (0.62 g, 7.0 mmol) and THF (20 mL). After warming to -20° C. for 5 minutes, the reaction was re-cooled to -78° C. and freshly prepared 1-(3-cyanophenyl)-3-methylpyrazol-5-yl carboxylic acid chloride (1.4 g, 5.7 mmol) in THF (15 mL) was added. The reaction was allowed to warm to room temperature and stirred 18h. The reaction was diluted with ethyl acetate and washed with brine and dried (Na₂ SO₄). Purification by chromatography on silica gel using 2:1 hexanes/ethyl acetate as eluent afforded 0.62 g(28%) of the title compound. ¹ HNMR(CDCl₃)δ: 7.67 (dd, j=1.83, 6.96 Hz, 1H), 7.62 (s, 1H), 7.54 (m, 2H), 7.49 (d, j=8.42 Hz, 2H), 7.13 (d, j=8.42 Hz, 2H), 6.90 (s, 1H), 4.10 (s, 2H), 2.39 (s, 3H) ppm; MS (NH3-CI) 380-382 (M+H)+, 397-399 (M+NH₄)⁺.

Part B: To the product from part A (0.6 g, 1.6 mmol) was added 2-t-butylaminosulfonyl phenylboronic acid (0.57 g, 2.2 mmol), 2M sodium carbonate (3 mL) in 1:1 ethanol/toluene. The reaction mixture was degassed with a stream of nitrogen for 15 minutes. Tetrakistriphenylphosphine palladium (0.3 g) was added and the reaction was heated to reflux for 24h. The reaction was cooled, filtered and concentrated. The aqueous residue was extracted with ethyl acetate, washed with brine and dried (MgSO₄). Purification by chromatography on silica gel using 3:1 hexanes/ethyl acetate as eluent afforded 0.62 g (77%) of the title compound. ¹ HNMR(CDCl₃)δ: 8.18 (dd, j=1.46, 7.69 Hz, 1H), 7.68 (m, 2H), 7.58 (m, 2H), 7.52 (d+m, j=8.40, Hz, 4H), 7.34 (d+m, j=8.05 Hz, 3H), 6.95 (s, 1H), 4.21 (s, 2H), 3.48 (s, 1H), 2.40 (s, 3H), 0.97 (s, 9H) ppm; MS (ESI) 513.2 (M+H)⁺, 535.2 (M+Na)⁺.

Part C: Standard Pinner amidine reaction sequence then afforded the title compound as colorless crystals. ¹ HNMR(DMSO-d₆)δ: 9.39 (s, 1.5H), 9.03 (s, 1.5H), 8.03 (dd, j=7.32, 1.83 Hz, 1H), 7.85 (m, 2H), 7.68 (m, 2H), 7.59 (m, 2H), 7.44 (s, 1H), 7.36 (m, 7H), 4.34 (s, 2H), 2.34 (s, 3H) ppm; HRMS 474.159987 (calcd), 474.161536 (obs.); Analysis calcd for C₂₅ H₂₃ N₅ O₃ S(TFA) (H2O)0.5: C:54.36, H:4.22, N:11.74, found C:54.39, H:3.87, N:11.65.

EXAMPLE 77 1-(3-aminocarbonylphenyl)-5-[5-[(2'-aminosulfonylphen-1-yl)pyridin-2-yl]aminocarbonyl]-3-methylpyrazole, Trifluoroacetic Acid Salt

1-(3-cyanophenyl)-5-[[5-[(2'-t-butylaminosulfonylphen-1-yl)pyridin-2-yl]aminocarbonyl]-3-methylpyrazole was converted to the title amide by the procedure described previously (Example 75); ¹ HNMR(DMSO-d₆)δ: 11.15 (s, 1H), 8.35 (d, j=2.19 Hz, 1H), 8.12 (m, 4H), 7.90 (m, 1H), 7.81 (dd, j=2.20, 8.79 Hz, 1H), 7.66 (m, 2H), 7.55 (m, 2H), 7.48 (s, 1H), 7.41 (m, 3H), 7.08 (s, 1H), 2.32 (s, 3H) ppm; HRMS 477.134500 (calcd), 477.135223 (obs.).

EXAMPLE 78 1-(3-amidinophenyl)-5-[[5-(2'-t-butylaminosulfonylphenyl) pyrimidin-2-yl]aminocarbonyl]-3-trifluoromethyl-pyrazole, Trifluoroacetic Acid Salt

Part A: 1-(3-cyanophenyl)-5-[[5-(2'-t-butylaminosulfonylphenyl)pyrimidin-2-yl]aminocarbonyl]-3-trifluoromethyl pyrazole was obtained via standard coupling protocols. ¹ HNMR(CDCl₃) δ: 9.13 (s, 1H), 8.64 (s, 2H), 8.22 (dd, j=1.47, 7.69 Hz, 1H), 7.89 (m, 1H), 7.85 (m, 1H), 7.75 (dd, j=1.46, 6.59 Hz, 1H), 7.65 (m, 3H), 7.30 (m, 2H), 4.60 (s, 1H), 1.13 (s, 9H) ppm; MS (ESI) 570.1 (M+H)+, 592.1 (M+Na)⁺.

Part B: Standard Pinner amidine reaction sequence then afforded the title compound as colorless crystals. ¹ HNMR(DMSO-d₆)δ: 11.64 (s, 1H), 9.46 (s, 1.5H), 9.11 (s, 1.5H), 8.63 (s, 2H), 8.09 (dd, j=7.69, 1.83 Hz, 1H), 8.04 (s, 1H), 7.96 (m, 2H), 7.81 (m, 2H), 7.76 (m, 2H), 7.42 (dd, j=1.46, 8.79 Hz, 1H), 7.32 (s, 1H), 1.03 (s, 9H) ppm; HRMS 587.180069 (calcd), 587.177999 (obs.);Analysis calcd for C₂₆ H₂₅ F₃ N₈ O₃ S(TFA)1.1: C:47.57, H:3.69, N:15.74, found C:47.51, H:3.54, N:15.41.

EXAMPLE 79 1-(3-amidinophenyl)-5-[[5-(2'-aminosulfonylphenyl)pyrimidin-2-yl]aminocarbonyl]-3-trifluoromethyl-pyrazole, Trifluoroacetic Acid Salt

1-(3-cyanophenyl)-5-[[5-(2'-t-butylaminosulfonylphenyl)pyrimidin-2-yl]-aminocarbonyl]-3-trifluoromethyl-pyrazole, (0.275 g, 0.39 mmol) was heated to reflux in TFA for 1h. Removal of TFA and purification by HPLC afforded 0.2 g (80%) title compound. ¹ HNMR(DMSO-d₆) δ: 11.63 (s, 1H), 9.46 (s, 1.5H), 9.42 (s, 1.5H), 8.66 (s, 2H), 8.08 (m, 2H), 7.96 (m, 2H), 7.83 (s, 1H), 7.81 (m, 1H), 7.72 (m, 2H), 7.54 (s, 2H), 7.45 (m, 1H) ppm; HRMS 531.117468 (calcd), 531.117523 (obs.); Analysis calcd for C₂₂ H₁₇ F₃ N₈ O₃ S (TFA) 1.1 (H₂ O)0.5: C:43.71, H:2.90, N:16.85, found C:43.99, H:2.62, N:16.54.

EXAMPLE 80 1-(3-aminocarbonylphenyl)-5-[[5-(2'-aminosulfonylphenyl)pyrimidin-2-yl]aminocarbonyl]-3-trifluoromethylpyrazole

1-(3-cyanophenyl)-5-[[5-(2'-t-butylaminosulfonylphenyl) pyrimidin-2-yl]aminocarbonyl]-3-trifluoromethyl pyrazole (0.5 g, 0.8 mmol) was cooled to 0° C. and con. H₂ SO₄ (5 mL) was added. The reaction was kept cold 24h. Ice water was added and the precipitated solid was collected, dissolved in ethyl acetate and dried (MgSO₄). Purification, first, by chromatography on silica gel using 1-10% methanol/methylene chloride as eluent, then by HPLC afforded 72 mg (14%) of the title amide. ¹ HNMR(DMSO-d₆)δ: 11.59 (s, 1H), 8.64 (s, 2H), 8.16 (s, 1H), 8.03 (s, 3H), 7.72 (m, 4H), 7.64 (d, j=7.33 Hz, 1H), 7.58 (m, 1H), 7.51 (s, 2H), 7.43 (d, j=7.33 Hz, 1H) ppm; HRMS 532.096112 (calcd), 532.098037 (obs.); Analysis calcd for C₂₂ H₁₆ F₃ N₇ O₄ S(TFA)0.5: C:46.99, H:2.83, N:16.66, found C:46.86, H:2.74, N:16.35.

EXAMPLE 81 1-(3-cyanophenyl)-5-[((4'-(imidazol-1-yl)phenyl)aminocarbonyl]-3-trifluoromethylpyrazole, Trifluoroacetic Acid Salt

Part A: 1-(3-cyanophenyl)-3-trifluoromethyl-pyrazol-5-yl carboxylic acid (0.5 g, 1.8 mmol) was coupled with 4-imidazoyl aniline (0.3 g, 1.8 mmol) by standard conditions and purified by HPLC to afford 0.67 g(71%) product. ¹ HNMR(DMSO-d₆)δ: 9.55 (s, 1H), 8.22 (d, j=5.49 Hz, 2H), 8.04 (d, j=7.69 Hz, 1H), 7.96 (d, j=8.06 Hz, 1H), 7.89 (s+d, j=8.79 Hz, 3H), 7.80 (m, 4H) ppm; HRMS 423.118119 (calcd), found 423116015 (obs.); Analysis calcd for C₂₁ H₁₃ F₃ N₆ O(TFA): C:51.50, H:2.63, N:15.67, found C:51.52, H:2.71, N:15.49.

Part B: 1-(3-cyanophenyl)-5-((4'-(imidazol-1-yl)phenyl) aminocarbonyl]-3-trifluoromethylpyrazole was subjected to standard Pinner and purification conditions to afford title amidine (79%) as colorless crystals. ¹ HNMR(DMSO-d₆)δ: 11.02 (s, 1H), 9.46 (s, 1.5H), 9.42 (s.1H), 9.22 (s, 1.5H), 8.17 (s, 1H), 8.06 (s, 1H), 7.97 (t, j=7.69 Hz, 2H), 7.88 (d, j=8.79 Hz, 2H), 7.80 (m, 3H), 7.79 (d, j=9.0 Hz, 2H) ppm; HRMS 440.144668 (calcd), 440.144557 (obs.).

EXAMPLES 82 AND 83 1-(3-amidinophenyl)-5-[(4'-(morpholin-1-yl)phenyl)-aminocarbonyl]-3-trifluoromethylpyrazole, Trifluoroacetic Acid Salt (Example 82) and 1-(3-aminocarbonylphenyl)-5-[(4'-(morpholin-1-yl)phenyl)aminocarbonyl]-3-trifluoromethylpyrazole, Trifluoroacetic Acid Salt (Example 83)

Part A: 1-(3-cyanophenyl)-3-trifluoromethyl-pyrazol-5-yl carboxylic (0.34 g, 1.2 mmol) was coupled with 4-(4-morpholino) aniline (0.22 g, 1.2 mmol) by standard conditions to afford 0.53 g (69%) product. ¹ HNMR(CDCl₃)δ: 9.63 (s, 1H), 7.85 (d, j=1.46 Hz, 1H), 7.79 (m, 1H), 7.74 (d, j=7.69 Hz, 1H), 7.60 (t, j=8.06 Hz, 1H), 7.53 (d, j=8.79 Hz, 2H), 7.37 (s, 1H), 6.89 (d, j=9.15 Hz, 2H), 3.87 (m, 4H), 3.87 (m, 4H) ppm; MS (ESI) 442.1 (M+H)⁺.

Part B: Synthesis of 1-(3-amidinophenyl)-5-[(4'-(morpholin-1-yl)phenyl) aminocarbonyl]-3-trifluoro-methylpyrazole, Trifluoroacetic Acid Salt

The nitrile from part A was subjected to standard Pinner conditions to afford 65% yield of the amidine as colorless crystals. ¹ HNMR(DMSO-d₆)δ: 10.56 (s, 1H), 9.45 (s, 1.5H), 9.13 (s, 1.5H), 8.02 (s, 1H), 7.94 (m, 2H), 7.79 (t, j=7.69 Hz, 1H), 7.69 (s, 1H), 7.51 (d, j=9.16 Hz, 2H), 6.94 (d, j=8.80 Hz, 2H), 3.74 (m, 4H), 3.08 (m, 4H) ppm; HRMS 459.175634 (calcd), 459.173592 (obs.); Analysis calcd for C₂₂ H₂₁ F₃ N₆ O₂ (TFA)2.7 (H₂ O)0.1: C:42.85, H:3.14, N:10.94, found C:42.87, H:2.78, N:10.80.

Part C: The amide was also isolated from the Pinner reaction in the part B. ¹ HNMR(DMSO-d₆)δ: 10.54 (s, 1H), 8.15 (m, 2H), 7.68 (m, 1H), 7.60 (s, 1H), 7.55 (m, 1H), 7.50 (d, j=8.78 Hz, 2H), 6.94 (d, j=8.78 Hz, 2H), 3.73 (m, 4H), 3.07 (m, 4H) ppm; MS (ESI) 460.1 (M+H)⁺, 482 (M+Na)⁺.

EXAMPLES 84 AND 85 1-(3-amidinophenyl)-5-[[2'-(2'-aminosulfonylphenyl)pyridin-2-yl]aminocarbonyl]-3-trifluoromethyl Pyrazole, Trifluoroacetic Acid Salt (Example 84) and 1-(3-aminocarbonylphenyl)-5-[[5-(2'-aminosulfonylphenyl)pyridin-2-yl]aminocarbonyl]-3-trifluoromethylpyrazole, Trifluoroacetic Acid Salt (Example 85)

Part A: 1-(3-cyanophenyl)-5-[[5-[(2'-t-butylaminosulfonyl)-1-yl) pyridin-2-yl]-aminocarbonyl]-3-trifluoromethyl pyrazole. ¹ HNMR(CDCl₃) δ: 8.75 (s, 1H), 8.35 (d, j=1.83 Hz, 1H), 8.21 (m, 2H), 7.87 (m, 4H), 7.66 (t, j=7.69 Hz, 1H), 7.59 (m, 2H), 7.29 (m, 2H), 4.30 (s, 1H), 1.11 (s, 9H) ppm; MS (ESI) 569.1 (M+H)⁺, 591.1 (M+Na)⁺.

Part B: Standard Pinner amidine reaction sequence then afforded the title compound as colorless crystals; ¹ HNMR(DMSO-d₆) δ: 11.46 (s, 1H), 9.47 (s, 1.5H), 9.21 (s, 1.5H), 8.39 (d, j=1.84 Hz, 1H), 8.06 (m, 2H), 7.97 (m, 4H), 7.82 (m, 2H), 7.68 (m, 2H), 7.45 (s, 2H), 7.40 (dd, j=2.20 Hz, 7.69 Hz, 1H) ppm; MS (ESI) 530.1 (M+H)+. Analysis calcd for C₂₃ H₁₈ F₃ N₇ O₃ S(TFA)₂ : C:42.81, H:2.66, N:12.44, found C:42.99, H:2.44, N:12.77.

Part C: The amide was also isolated from the Pinner reaction in the part B; ¹ HNMR(DMSO-d₆) δ: 11.42 (s, 1H), 8.37 (d, 1H), 8.06 (s, 1H), 8.03 (m, 4H), 7.82 (m, 2H), 7.70 (m, 4H), 7.56 (s, 1H), 7.42 (s, 2H), 7.39 (dd, j=7.69, 2.2 Hz, 1H) ppm; HRMS 531.106235 (calcd), 531.108937 (obs.).

EXAMPLE 86 1-(3-amidinophenyl)-5-[(4'-(3-methyltetrazol-1-yl)phenyl) aminocarbonyl]-3-trifluoromethylpyrazole, Trifluoroacetic Acid Salt

Part A: Synthesis of 4-tetrazoyl Nitrobenzene

4-Nitrobenzonitrile (2 g, 13.5 mmol), sodium azide (0.92 g, 14 mmol), and tributyltin chloride (3.8 mL, 14 mmol) were combined in toluene (30 mL) and heated to reflux 18h. The reaction mixture was extracted with excess 1N NaOH. The aqueous layer was cooled, acidified with con. HCl, and the precipitated solid was filtered off and dried in vacuo. The aqueous layer was extracted with ethyl acetate, combined with the solid and dried (MgSO4) to afford 1.4 g (56%). ¹ HNMR(DMSO-d6)δ: 8.48 (d, j=8.79 Hz, 2H), 8.34 (d, j=8.79 Hz, 2H) ppm; MS (ES-) 190.0 (M-H).

Part B: To 4-tetrazoyl nitrobenzene (1.16 g, 6.1 mmol) and iodomethane (0.53 mL, 8.5 mmol) in DMF (10 mL) at 0° C. was added 60% sodium hydride (0.29 g, 7.3 mmol). The reaction was allowed to warm to room temperature and stirred 24h. The reaction was quenched with water and extracted with ethyl acetate and dried(MgSO₄). Purification by chromatography on silica gel using 4:1 hexanes/ethyl acetate as eluent afforded 0.9 g (72%) of the major isomer, 4-(3-methyltetrazole) nitrobenzene. ¹ HNMR(CDCl₃)δ: 8.38 (d, j=9.16 Hz, 2H), 8.35 (d, j=9.52 Hz, 2H), 4.45 (s, 3H) ppm; MS (NH₃ -CI) 206 (M+H)⁺, 176 (M+H-NO).

Part C: 4-(3-methyltetrazole) nitrobenzene (0.67 g, 3.3 mmol) was placed in ethanol (15 mL) and trifluoroacetic acid (1 mL). A catalytic amount of 10% Palladium on carbon was added and the mixture was placed under a hydrogen balloon. The reaction was stirred 4h, then filtered and concentrated. The 4-(3-methyltetrazole) aniline trifluoroacetic acid salt obtained (MS 176 (M+H)⁺) was used directly in the next step. 4-(3-Methyltetrazole) aniline trifluoroacetic acid salt and 1-(3-cyanophenyl)-3-trifluoromethylpyrazol-5-yl carboxylic acid were coupled by standard conditions to give 1-(3-cyanophenyl)-5-[(4'-(3-methyltetrazol-1-yl)phenyl) aminocarbonyl]-3-trifluoromethylpyrazole. ¹ HNMR(CDCl₃)δ: 10.45 (s, 1H), 8.11 (d, j=8.79 Hz, 2H), 7.86 (s, 1H), 7.82 (d, j=8.79 Hz, 2H), 7.77 (dd, j=7.69, 1.46 Hz, 2H), 7.63 (t, j=7.69 Hz, 1H), 7.50 (s, 1H), 4.40 (s, 3H) ppm; MS (ESI) 439 (M+H)⁺, 460.9 (M+Na)⁺.

Part D: The nitrile from part C was subjected to ths standard Pinner conditions to give 1-(3-amidinophenyl)-5-[(4'-(3-methyltetrazol-1-yl)phenyl) aminocarbonyl]-3-trifluoromethylpyrazole, trifluoroacetic acid salt. ¹ HNMR(DMSO-d₆)δ: 10.97 (s, 1H), 9.47 (s, 1.5H), 9.24 (s, 1.5H), 8.07 (d, j=8.79 Hz, 2H), 8.06 (m, 1H), 7.97 (m, 2H), 7.86 (d, j=8.78 Hz, 2H), 7.80 (m, 2H), 4.41 (s, 3H) ppm; HRMS 456.150816 (calcd), 456.152474 (obs.); Analysis calcd for C₂₀ H₁₆ F₃ N₉ O(TFA)1.2: C:45.43, H:2.93, N:21.29, found C:45.37, H:3.18, N:21.39.

EXAMPLE 87 1-(3-amidinophenyl)-5-(2'-napthylaminosulfonyl)-3-methylpyrazole, Trifluoroacetic Acid Salt

Part A: To 5-amino-1-(3-cyanophenyl)-3-methylpyrazole (0.5 g, 2.5 mmol) in methylene chloride (15 mL) was added 2-napthylsulfonyl chloride (0.63 g, 2.8 mmol) and triethylamine (0.46 mL, 3.3 mmol). The reaction was stirred 18h at room temperature, but did not appear complete by TLC. A few crystals of N,N-dimethylaminopyridine were added and the reaction was heated to reflux for 5h. The reaction was cooled, diluted and washed with 1N HCl, sat'd NaHCO₃, brine and dried(MgSO₄). Crude NMR and Mass Spectrum indicated that the major product was the bis-sulfonamide, MS (ESI) 579 (M+H)⁺, 601 (M+Na)⁺.

Part B: The crude bis-sulfonamide from part A was subjected to the standard Pinner conditions and purified by HPLC to afford 0.3 g (50%) of the desired mono-sulfonamide title compound, ¹ HNMR(DMSO-d₆)δ: 9.36 (s, 1.5H), 9.07 (s, 1.5H), 8.29 (s, 1H), 8.14 (d, j=7.69 Hz, 1H), 8.09 (t, j=8.79 Hz, 2H), 7.86 (s, 1H), 7.79 (m, 6H), 7.60 (d, j=7.69 Hz, 1H), 5.79 (s, 1H), 2.12 (s, 3H) ppm; HRMS 406.133772 (calcd), 406.133617 (obs.).

EXAMPLE 88 1-(3-amidinophenyl)-5-[(4-bromophenyl)aminosulfonyl]-3-methylpyrazole, Trifluoroacetic Acid Salt

Part A: To 5-amino-1-(3-cyanophenyl)-3-methylpyrazole (0.5 g, 2.5 mmol) in methylene chloride (15 mL) was added 4-bromobenzenesulfonyl chloride (0.7 g, 2.8 mmol) and triethylamine (0.46 mL, 3.3 mmol). The reaction was stirred 18h at room temperature, but did not appear complete by tlc. A few crystals of N,N-dimethylaminopyridine were added and the reaction was heated to reflux for 5h. The reaction was cooled, diluted and washed with 1N HCl, sat'd NaHCO₃, brine and dried(MgSO₄). Crude NMR and Mass Spectrum indicated that the major product was the bis-sulfonamide, MS (ESI) 634-636.6 (M+H)⁺, 655-657.2 (M+Na)⁺.

Part B: The crude bis-sulfonamide from part A was subjected to the standard Pinner conditions and purified by HPLC to afford 0.22 g (44%) of the desired mono-sulfonamide title compound, ¹ HNMR(DMSO-d₆)δ: 9.40 (s, 1.5H), 9.18 (s, 1.5H), 7.88 (s, 1H), 7.79 (m, 1H), 7.74 (d, j=8.40 Hz, 2H), 7.69 (m, 2H), 7.53 (d, j=8.42 Hz, 2H), 5.89 (s, 1H), 2.17 (s, 3H) ppm; HRMS 434.028633 (calcd), 434.029892 (obs.).

EXAMPLE 89 1-(3-aminomethylphenyl)-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-methylpyrazole, Trifluoroacetic Acid Salt

To 1-(3-cyanophenyl)-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl) aminocarbonyl]-3-methylpyrazole (0.19 g, 0.41 mmol) was added ethanol (20 mL), TFA (0.5 mL), and 10% Palladium on carbon (10 mg). The mixture was stirred under H2 (1 atmos.) for 18h. The reaction was filtered, concentrated and purified by HPLC to afford 17 mg (9%) of the title compound. ¹ HNMR(DMSO-d₆)δ: 10.66 (s, 1H), 8.22 (brd, 2H), 8.03 (dd, j=1.47, 6.22 Hz, 1H), 7.70 (d, j=8.79 Hz, 2H), 7.67 (m, 2H), 7.64 (m, 5H), 7.37 (d, j=8.43 Hz, 2H), 7.32 (m, 2H), 6.93 (s, 1H), 4.13 (d, j=4.03 Hz, 2H), 2.33 (s, 3H) ppm; HRMS 462.159987 (calcd), 462.158938 (found).

EXAMPLE 90 1-(3-aminomethylphenyl)-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-trifluoromethylpyrazole, Trifluoroacetic Acid Salt

1-(3-cyanophenyl)-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl) aminocarbonyl]-3-trifluoromethylpyrazole was reduced by hydrogenation to the title compound, ¹ HNMR(DMSO-d₆)δ: 10.89 (s, 1H), 8.25 (brd s, 1H), 8.04 (d, j=7.33 Hz, 1H), 7.75 (s, 1H), 7.69 (d+s, j=6.96 Hz, 3H), 7.60 (m, 4H), 7.39 (d, j=8.43 Hz, 2H), 7.32 (s+d, j=6.94 Hz, 3H), 4.17 (d, j=5.49 Hz, 2H) ppm; HRMS 516.131721 (calcd), 516.130109 (obs.); Analysis calcd for C₂₄ H₂₀ F₃ N₅ O₃ S(TFA)1.2: C:48.61, H:3.28, N:10.74, found C:48.35, H:3.18, N:10.69.

EXAMPLE 91 1-(3-amidinophenyl)-3-methyl-5-[((2'-trifluoromethylphenyl)pyrid-2-yl)aminocarbonyl]pyrazole, Trifluoroacetic Acid Salt

The title compound was prepared as colorless crystals following the standard Pinner amidine reaction sequence and purification protocols outlined previously. ¹ HNMR(DMSO)δ: 11.21 (s, 1H); 9.39 (s, 2H); 9.11 (s, 2H); 8.31 (s, 1H); 8.00 (d, 1H); 7.93 (s, 1H); 7.86-7.63 (m, 7H); 7.45 (d, 1H); 7.16 (s, 1H); 2.29 (s, 3H) ppm; LRMS (ESI) 465.3 (M+H)+HRMS for C24H20N6F3O1 465.165069 (calcd), 465.165566 (obs).

EXAMPLE 92 1-(3-amidinophenyl)-3-methyl-5-[((2'-aminosulfonyl-1-yl)pyrimid-5-yl)aminocarbonyl]pyrazole, Trifluoroacetic Acid Salt

The title compound was prepared as colorless crystals following the standard Pinner amidine reaction sequence and purification protocols outlined previously; ¹ HNMR(DMSO)δ: 11.39 (s, 1H); 9.43 (s, 2H); 9.08 (s, 2H); 8.65 (s, 2H); 8.08-8.05 (m, 1H); 7.96 (s, 1H); 7.83 (m, 1H); 7.78-7.68 (m, 4H); 7.54 (s, 2H); 7.46-7.43 (m, 1H); 7.09 (s, 1H); 2.33 (s, 3H), ppm; LRMS (ESI) 477.2 (M+H)+;HRMS for C₂₂ H₂₁ N₈ O₃ S₁ 477.148419 (calcd), 477.146755 (obs).

EXAMPLE 93 1-(3-amidinophenyl)-3-methyl-5-[(2'-fluoro-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole, Trifluoroacetic Acid Salt

The title compound was prepared as colorless crystals following the standard Pinner amidine reaction sequence and purification protocols outlined previously; ¹ HNMR(DMSO)δ: 10.68 (s, 1H); 9.43 (s, 2H); 9.13 (s, 2H); 7.96 (s,1H); 7.83-7.67 (m, 6H); 7.55 (d, 2H); 7.41 (m, 1H); 7.33-7.27 (m, 2H); 7.05 (s, 1H); 2.35 (s, 3H) ppm; LRMS (ESI) 414.3 (M+H)+;HRMS for C₂₄ H₂₁ N₅ O₁ F₁ 414.173014 (calcd); 414.172475 (obs).

EXAMPLE 94 1-(3-amidinophenyl)-3-methyl-5-[3-chloro-(2'-fluoro-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole, Trifluoroacetic Acid Salt

The title compound was prepared as colorless crystals following the standard Pinner amidine reaction sequence and purification protocols outlined previously; ¹ HNMR(DMSO)δ: 10.43 (s, 1H): 9.43 (S. 2H); 9.10 (s, 2H); 7.95 (s, 1H); 7.82 (m, 2H); 7.73 (m, 2H); 7.68-7.54 (m, 3H); 7.46 (m, 1H); 7.38-7.30 (m, 2H); 7.07 (s, 1H); 2.35 (s, 3H) ppm; LRMS (ESI) 448.2 (M+H)+;HRMS for C₂₄ H₂₀ N₅ OFCl 448.134041 (calcd), 448.133737 (obs).

EXAMPLE 95 1-(3-amidinophenyl)-3-methyl-5-[3-fluoro-(2'-fluoro-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole, Trifluoroacetic Acid Salt

The title compound was prepared as colorless crystals following the standard Pinner amidine reaction sequence and purification protocols outlined previously; ¹ HNMR(DMSO)δ: 10.47 (s, 1H): 9.43 (s, 2H); 9.09 (s, 2H): 7.96 (s, 1H); 7.87-7.60 (m, 6H); 7.52 (m, 1H); 7.46 (d, 1H); 7.30 (d, 1H); 7.18 (d, 1H); 7.07 (s, 1H); 2.34 (s, 3H) ppm; LRMS (ESI) 482.2 (M+H)+; HRMS for C₂₅ H₂ N₅ OF₄ 482.160398 (calcd); 482.157655 (obs).

EXAMPLE 96 1-(3-amidinophenyl)-3-methyl-5-[3-fluoro-(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole, Trifluoroacetic Acid Salt

The title compound was prepared as colorless crystals following the standard Pinner amidine reaction sequence and purification protocols outlined previously; ¹ HNMR(DMSO) δ: 10.45 (s, 1H); 9.43 (s, 2H); 9.09 (s, 2H); 8.04 (m, 1H); 7.96 (s, 1H); 7.80 (m, 2H); 7.73 (d, 1H); 7.65 (m, 3H); 7.43 (s, 2H); 7.36-7.29 (m, 2H); 7.22 (m, 1H); 7.06 (s, 1H); 2.34 (s, 3H) ppm; LRMS (ESI) 493.2 (M+H)+;HRMS for C₂₄ H₂₂ N₆ O₃ SF 493.145814 (calcd), 493.146092 (obs).

EXAMPLE 97 1-(3-amidinophenyl)-3-methyl-5-[5-(2'-fluorophen-1-yl)pyrid-2-yl]aminocarbonyl]pyrazole, Trifluoroacetic Acid Salt

The title compound was prepared as colorless crystals following the standard Pinner amidine reaction sequence and purification protocols outlined previously; ¹ HNMR(DMSO) δ: 11.25 (s, 1H); 9.43 (s, 2H); 9.09 (s, 2H); 8.59 (s, 1H); 8.10-8.07 (d, j=8.79, 1H); 8.02-7.96 (m, 2H); 7.85-7.79 (m, 2H): 7.73-7.70 (d, j=8.06, 1H); 7.64-7.59 (m, 1H); 7.49-7.44 (m, 1H); 7.39-7.31 (m, 2H); 7.21 (s, 1H): 2.33 (s, 3H) ppm; LRMS (ESI) 415.2 (M+H)+; HRMS for C₂₃ H₂ ON₆ F 415.168263 (calcd); 425.168444 (obs).

EXAMPLE 98 1-(3-amidinophenyl)-3-methyl-5-[[5-(2'-tertbutylaminosulfonylphenyl)pyrimid-2-yl]aminocarbonyl]pyrazole, Trifluoroacetic Acid Salt

The title compound was prepared as colorless crystals following the standard Pinner amidine reaction sequence and purification protocols outlined previously; ¹ HNMR(DMSO)δ: 11.40 (s, 1H); 9.43 (s, 2H); 9.08 (s, 2H); 8.62 (s, 2H); 8.09-8.06 (m, 1H); 7.95 (s, 1H); 7.83-7.65 (m, 6H); 7.43-7.40 (m, 1H); 7.08 (s, 1H); 2.32 (s, 3H); 1.04 (s, 9H) ppm; LRMS (ESI) 533.3 (M+H)+; HRMS for C₂₆ H₂₉ N₈ O₃ S 533.208334 (calcd), 533.207170 (obs).

EXAMPLE 99 1-(3-amidinophenyl)-3-methyl-5-[[5-(2'-aminosulfonylphenyl)-[1,6]-dihydropyrimid-2-yl]aminocarbonyl]pyrazole, Trifluoroacetic Acid Salt

The title compound was prepared as colorless crystals following the standard Pinner amidine reaction sequence and purification protocols outlined previously; ¹ HNMR(DMSO) δ: 9.95 (s, 1H); 9.38 (s, 2H); 9.29 (s, 1H); 9.25 (s, 2H); 7.95-7.92 (m, 2H); 7.84 (d, j=7.81,₁ H); 7.79 (d, j=8.79, 1H); 7.70-7.66 (t, j=8.06, j=7.81, 1H); 7.58-7.56 (t, j=7.57, 1H); 7.54-7.49 (t, j=7.57, 1H); 7.48 (s, 2H); 7.40 (d, j=7.57, 1H); 6.86 (s, 1H); 6.13 (s, 1H); 4.24 (s, 2H); 2.28 (s, 3H) ppm; LRMS (ESI) 579.2 (M+H)+;HRMS for C₂₂ H₂₃ N₈ O₃ S 579.161384 (calcd), 579.161293 (obs).

EXAMPLE 100 1-(3-amidinophenyl)-3-methyl-5-[(4-(pyrid-3'-yl)phen-1-yl)aminocarbonyl]pyrazole, Trifluoroacetic Acid Salt

The title compound was prepared as colorless crystals following the standard Pinner amidine reaction sequence and purification protocols outlined previously; ¹ HNMR(DMSO) δ: 10.71 (s, 1H); 9.43 (s, 2H); 9.11 (s, 2H); 8.98 (s, 1H); 8.64 (m, 1H); 8.28-8.25 (d, J=8.43, 1H); 7.97 (s, 1H); 7.84-7.06 (m, 8H); 7.06s, 1H); 2.35 (s, 3H), ppmLRMS (ESI) 379.2 (M+H)+; HRMS for C₂₃ H₂₁ N₆ O 379.177685 (calcd), 379.176514 (obs).

EXAMPLE 101 1-(3-amidinophenyl)-3-methyl-5-[[2-(2'-pyridyl)ethyl]aminocarbonyl]pyrazole, Trifluoroacetic Acid Salt

The title compound was prepared as colorless crystals following the standard Pinner amidine reaction sequence and purification protocols outlined previously; ¹ HNMR(DMSO) δ: 9.40 (s, 2H); 9.16 (s, 2H); 8.81 (m, 1H); 8.68 (m, 1H); 8.09 (m, 1H); 7.85 (s, 1H); 7.80-7.77 (d, j=8.06, 1H); 7.64-7.54 (m, 4H); 6.72 (s, 1H); 3.61-3.55 (q, 2H); 3.09-3.05 (t, 2H); 2.26 (s, 3H), ppm; LRMS (ESI) 349.1 (M+H) +; HRMS for C₁₉ H₂₁ N₆ O 349.177685 (calcd); 349.175374 (obs).

EXAMPLE 102 1-(3-amidinophenyl)-3-methyl-5-[(3-phenylpropyl)aminocarbonyl]pyrazole, Trifluoroacetic Acid Salt

The title compound was prepared as colorless crystals following the standard Pinner amidine reaction sequence and purification protocols outlined previously; ¹ HNMR(DMSO) δ: 9.41 (s, 2H); 9.11 (s, 2H); 8.72 (m, 1H); 7.88 (s, 1H); 7.81-7.77 (m, 1H); 7.68 (m, 2H); 7.31-7.18 (m, 5H); 6.77 (s, 1H); 3.21-3.14 (q, j=6.60, 2H); 2.62-2.57 (t, j=7.69, 2H); 2.28 (s, 3H); 1.82-1.73 (qu, j=7.32, 2H) ppm; LRMS (ESI) 362.1 (M+H)+; HRMS for C₂₁ H₂₄ N₅ O 362.198086 (calcd); 362.197157 (obs).

EXAMPLE 103 1-(3-amidinophenyl)-3-methyl-5-[4-(pyrid-2'-yl)phen-1-ylaminocarbonyl]pyrazole, Trifluoroacetic Acid Salt

The title compound was prepared as colorless crystals following the standard Pinner amidine reaction sequence and purification protocols outlined previously; ¹ HNMR(DMSO) δ: 10.70 (s, 1H); 9.43 (s, 2H); 9.08 (s, 2H); 8.66 (m, 1H); 8.10 (m, 2H); 7.96-7.88 (m, 3H); 7.84-7.76 (m, 4H); 7.73 (m, 1H); 7.38 (m, 1H); 7.06 (s, 1H); 2.35 (s, 3H) ppm; LRMS (ESI) 397.1 (M+H)+; HRMS for C₂₃ H₂₁ N₆ O 397.177685 (calcd); 397.179670 (obs).

EXAMPLE 104 1-(3-amidinophenyl)-3-methyl-5-[(4-(isopropyloxy)phenyl)aminocarbonyl]pyrazole, Trifluoroacetic Acid Salt

The title compound was prepared as colorless crystals following the standard Pinner amidine reaction sequence and purification protocols outlined previously; ¹ HNMR(DMSO) δ: 10.40 (s, 1H); 9.42 (s, 2H); 9.06 (s, 2H); 7.94 (S. 1H); 7.82 (d, j=7.32, 1H); 7.75-7.65 (m, 2H); 7.54 (d, j=9.16, 2H); 6.97 (s, 1H); 6.89 (d, j=8.79, 2H); 4.57-4.53 (m, 1H); 2.32 (s, 3H); 1.25 (s, 3H); 1.23 (s, 3H), ppm LRMS (ESI) 378.1 (M+H)+; HRMS for C₂₁ H₂₄ N₅ O₂ 378.193000 (calcd); 378.194610 (obs).

EXAMPLE 105 1-(3-amidinophenyl)-3-methyl-5-[(5-(2'-trifluoromethylphenyl)-pyrimidin-2-yl) aminocarbonyl]pyrazole, Trifluoroacetic Acid Salt

The title compound was prepared as colorless crystals following the standard Pinner amidine reaction sequence and purification protocols outlined previously; ¹ HNMR(DMSO) δ: 11.45 (s, 1H): 9.43 (s, 2H); 9.09 (s, 2H); 8.69 (s, 2H); 7.96 (s, 1H): 7.93 (d, j=8.06, 1H); 7.84-7.67 (m, 5H); 7.57 (d, j=7.69, 1H); 7.10 (s, 1H); 2.32 (s, 3H) ppm; LRMS (ESI) 466.1 (M+H)+; HRMS for C₂₃ H₁₉ N₇ F₃ O 466.163004 (calcd), 466.161823 (obs).

EXAMPLE 106 1-(3-amidinophenyl)-3-methyl-5-[(4-(piperidinosulfonyl)phenyl)aminocarbonyl]pyrazole, Trifluoroacetic Acid Salt

The title compound was prepared as colorless crystals following the standard Pinner amidine reaction sequence and purification protocols outlined previously; ¹ HNMR(DMSO) δ: 10.90 (s, 1H); 9.42 (s, 2H); 9.19 (s, 2H): 7.95 (m, 3H); 7.80 (m, 2H); 7.70 (m, 3H); 7.08 (s, 1H); 2.85 (m, 4H); 2.35) s, 3H); 1.54 (m, 4H); 1.35 (brd, 2H); ppm LRMS (ESI) (M+H)+467.1; HRMS for C₂₃ H₂₇ N₆ O₃ S 467.186536 (calcd); 467.185030 (obs).

EXAMPLE 107 1-(3-amidinophenyl)-3-methyl-5-[(4-(piperidinocarbonyl)phenyl)aminocarbonyl]pyrazole, Trifluoroacetic Acid Salt

The title compound was prepared as colorless crystals following the standard Pinner amidine reaction sequence and purification protocols outlined previously; ¹ HNMR(DMSO) δ: 10.69 (s, 1H); 9.43 (s, 2H); 9.12 (s, 2H); 7.95 (s, 1H); 7.83 (m, 1H): 7.77-7.96 (m, 4H); 7.37 (d, j=8.79, 2H); 7.04 (s, 1H); 3.31 (brd, 2H); 3.54 (brd, 2H); 2.34 (s, 3H); 1.60 (brd, 2H); 1.50 (brd, 4H) ppm; LRMS (ESI) 431.1 (M+H)+.

EXAMPLES 108 AND 109 1-(3-amidino-4-fluorophenyl)-3-methyl-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-pyrazole, Trifluoroacetic Acid Salt (Example 108) and 1-(3-aminocarbonyl-4-fluorophenyl)-3-methyl-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-pyrazole (Example 109)

Part A: Preparation of 2-fluoro-5-aminobenzonitrile

To a solution of 2-fluoro-5-nitrobenzonitrile (2.0 g, 12 mmol) in ethyl acetate(50 mL) was added stannous chloride (27.0 g, 120 mmol). The reaction mixture was stirred at reflux 1.5 h, then cooled to room temperature. Partitioned between ethyl acetate (150 mL) and saturated sodium bicarbonate(150 mL). Organic phase was separated and washed with water (5×75 mL), brine (75 mL); dried over sodium sulfate (anhy.); filtered and concentrated to give 2-fluoro-5-aminobenzonitrile (1.4 g) as pure compound.

Part B: Preparation of 3-cyano-4-fluorophenylhydrazine Tin Chloride

To a solution of 2-fluoro-5-aminobenzonitrile (1.4 g, 10.3 mmol) in HCl (conc., 15 mL) at 0° C. was added a solution of sodium nitrite (0.71 g, 10.3 mmol) in cold water (3 mL) dropwisely. After addition, the mixture was stirred at 0° C. 0.5 h, a solution of stannous chloride (6.95 g, 30.9 mmol) in cold water (5 mL) was added dropwisely. The slurry was cooled in refrigerate overnight, the solid was filtered and washed with brine (20 mL), petroleum ether:ether (2:1, 30 mL) and air dried to leave 3-cyano-4-fluorophenylhydrazine tin chloride (2.5 g).

Part C: Preparation of ethyl 1-(3-cyano-4-fluorophenyl)-3-methyl-pyrazol-5-yl Carboxylate

To a mixture of 3-cyano-4-fluorophenylhydrazine tin chloride (0.9 g, 2.65 mmol) in acetic acid (15 mL) was added oxime. The reaction mixture was brought to reflux overnight. Acetic acid was removed on rotary evaporator under reduced pressure. Residue was partitioned between ethylacetate (30 mL) and sodium bicarbonate (25 mL). Organic phase was separated and washed with water (3×20 mL), dried over sodium sulfate; filtered and concentrated; flash chromatography (ethylacetate:hexane, 1:5) to give ethyl 1-(3-cyano-4'-fluorophenyl)-3-methyl-pyrazol-5-yl carboxylate (0.7 g).

Part D: Preparation of 1-(3-cyano-4-fluorophenyl)-3-methyl-5-[(2'-tert-butylaminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-pyrazole

To a solution of biphenyl amine (167 mg, 0.55 mmol) in methylene chloride(5 mL) was added trimethyl aluminum (2.OM in hexane, 0.55 mL, 1.1 mmol) via syringe at 0° C. The mixture was slowly warmed to room temperature and stirred for 20 minutes followed by portionwise addition of a solution of ethyl 1-(3-cyano-4'-fluorophenyl)-3-methyl-pyrazol-5-yl carboxylate (100 mg, 0.37 mmol) in methylene chloride (5 mL). The reaction mixture was stirred at 45° C. under nitrogen overnight. Methylene chloride was removed, the residue quenched with HCl (10%, 5 mL), and partitioned between ethylacetate (20 mL) and HCl (10%, 15 mL). The organic phase was separated and washed with HCl (10%, 3×10 mL) and water(2×10 mL); dried over sodium sulfate; filtered and concentrated to leave 1-(3-cyano-4-fluorophenyl)-3-methyl-5-[(2'-tert-butylaminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-pyrazole (150 mg) as a pure compound. ¹ HNMR(CDCl₃)δ: 8.21 (s, 1H), 8.17-8.14 (m, 1H), 7.75 (d, 1H), 7.72 (t, 1H), 7.66 (d, 2H), 7.60-7.46 (m, 5H), 7.31-7.28 (m, 2H), 6.78 (s, 1H), 3.67 (s, 1H), 2.41 (s, 3H), 1.03 (s, 9H) ppm; ESI m/z (rel. intensity) 554 (M+Na, 100).

Part E: Preparation of 1-(3-amidino-4-fluorophenyl)-3-methyl-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-pyrazole, Trifluoroacetic Acid Salt and 1-(3-carboxamido-4-fluorophenyl)-3-methyl-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-pyrazole

1-(3-cyano-4-fluorophenyl)-3-methyl-5-[(2'-tert-butylaminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-pyrazole (150 mg) was dissolved in a saturated HCl solution of anhydrous methanol (10 mL). The reaction mixture was stirred at room temperature for 24h. Then methanol was evaporated. The residue was redissolved in methanol (10 mL) and excess ammonium carbonate added. The reaction mixture was stirred at room temperature overnight. Methanol was evaporated and the residue was purified via HPLC to afford 1-(3-amidino-4-fluorophenyl)-3-methyl-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-pyrazole as its TFA salt (20 mg). ¹ HNMR(CD₃ OD)δ: 8.07-8.04 (m, 3H), 7.63 (d, 2H), 7.58 (d, 2H), 7.42-7.55 (m, 2H), 7.38 (d, 2H), 7.35 (d, 2H), 6.80 (s, 1H), 2.34 (s, 3H) ppm; ESI m/z (rel. intensity) 493 (M+H, 100) and 1-(3-aminocarbonyl-4-fluorophenyl)-3-methyl-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-pyrazole (10 mg). ¹ HNMR(DMSO d₆)δ: 10.59 (s, 1H), 7.99 (dd, 1H), 7.81 (br, 1H), 7.72-7.67 (m, 2H), 7.63 (d, 2H), 7.60-7.49 (m, 4H), 7.38-7.26 (m, 4H), 7.21 (s, 2H), 6.90 (s, 1H), 2.29 (s, 3H). High resolution mass spectrum calcd. for C₂₄ H₂₀ FN₅ O₄ S (M+H):494.129829, found: 494.131923.

EXAMPLE 110 1-Methyl-3-(3-amidino)phenyl-4-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole

Part A: A mixture of ethyl-3-cyanobenzoylacetate (2.01 g) and N,N-dimethyldiethylacetal (50 mL) were heated to gentle reflux overnight. Evaporation of the solvent in vacuo afforded a thick viscous reddish oil which was redissolved in anhydrous methanol (50 mL). To this solution was then added N-methylhydrazine (0.43 g) dropwise. The reaction mixture was stirred at room temperature overnight. Then concentrated to a viscous oil containing a regioisomeric mixture of pyrazoles. Without any further purification the mixture of pyrazoles obtained above (0.45 g, 1.79 mmol) was added to a dichloromethane (50 mL) solution of 2'-tert-butylsulfonamide-1-aminobiphenyl (0.54 g, 1.79 mmol) and trimethylaluminum (5.37 mL, 10.7 mmol). The reaction mixture was stirred at room temperature overnight followed by quenching with dil. HCl (1N). The organics were extracted with ethylacetate (2×50 mL), dried (MgSO₄) and evaporated to a colorless residue. Silica gel column chromatography (dichoromethane:MeOH, 9:1) afforded regioisomeric mixtures of coupled pyrazoles. Preparatory HPLC reverse phase (acetonitrile:water gradient flow) allowed for the separation of pure 1-methyl-3-(3-cyano)phenyl-4-[(2'-tert-butylaminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole as a colorless oil (0.35 g); ¹ HNMR(CDCl₃)δ: 8.14 (d, 1H), 8.01 (s, 1H), 7.83-7.65 (m, 4H), 7.60-7.41 (m, 6H), 7.27 (m, 2H), 3.78 (s, 3H), 3.63 (s, 1H), 1.00 (s, 9H) ppm; ESI mass spectrum 536 (M+Na, 45), 514 (M+H, 100).

Part B: The product from part A was then subjected to the Pinner amidine reaction sequence as outlined in Example 10 to obtain after preparative HPLC separation and lyophilization colorless crystals of the title compound (0.15 g); ¹ HNMR(DMSO-d₆) δ: 9.90 (s, 1H), 9.37 (bs, 1.5H), 9.29 (bs, 1.5H), 8.24 (s, 1H), 8.00 (d, 1HO, 7.90 (bs, 2H), 7.84 (d, 1H), 7.73 (m, 1H), 7.69-7.50 (m, 4H), 7.37-7.27 (m, 3H0, 7.17 (bs, 1H), 3.98 (s, 3H) ppm; ESI mass spectrum m/z (rel. int.) 475.3 (M+H, 100).

EXAMPLE 111 1-(3-amidinophenyl)-5-[[4-(pyrazol-4'-yl)phen-1-yl]aminocarbonyl]pyrazole, Trifluoroacetic Acid Salt

Part A: 4-Iodopyrazole (20 mmol) was treated with Et₃ N (30 mmol) and (Boc)₂ O (22 mmol) in THF (60 mL) at r.t. for 2 hours to form N-Boc-4-iodopyrazole (5.88 g, 100%). N-Boc-4-iodopyrazolyle in THF (100 mL) was reacted with hexamethylditin (20 mmol) in the presence of Pd(Ph₃ P)₄ (1.1 g, 1 mmol) under nitrogen at 78° C. overnight. To it was added aqueous 10% KF and the resulting mixture was stirred for 30 minutes, and then filtered through a pad of Celite. The filtrate was extracted with EtOAc. The EtOAc layer was washed with water, and dried over MgSO₄. Filtration and concentration followed by purification of the mixture by column chromatography afforded the 3-trimethyltinpyrazole derivative (5 g, 75%) as a white solid.

Part B: The product from part A (10 mmol) was treated with with 4-nitrobromobenzene (10 mmol) in the presence of Pd(Ph₃ P)₄ (0.36 g, 0.3 mmol) under nitrogen at 78° C. overnight, followed by workup as described above afforded the 4-pyrazolo-nitrobenzene derivative (0.95 g, 33%). Hydrogenation (0.85 g, 2.94 mmol) in MeOH (150 mL) in the presence of Pd (5% on C, 0.09 g) at r.t. for 16 hours afforded the aniline derivative (0.76 g, 100%).

Part C: Standard coupling of the product from part B with the pyrazole acid chloride under reflux for 1.5 with Et₃ N (1 mL) followed by usual workup and purification afforded the coupled amide pyrazole-benzonitrile derivative (255 mg, 55%) which was subjected to the Pinner amidine sequence to afford after purification the title compound as colorless (148 mg, 70%). ¹ HNMR(CD₃ OD) δ: 7.93 (bs, 2H), 7.90-7.87 (m, 1H), 7.80 (td, J=7.4 Hz, J=1.2 Hz, 2H), 7.70 (t, J=7.8 Hz, 1H), 7.57 (d, J=7.4 Hz, 2H), 7.60-7.54 (m, 2H), 6.93 (d, J=1.9 Hz, 1H), 2.38 (s, 3H); ¹³ C NMR (CD₃ OD)δ: 167.92, 159.84, 151.36, 142.27, 139.28, 137.30, 131.43, 131.07, 130.51, 128.33, 126.99, 125.48, 122.48, 110.77, 13.29; ESMS: m/z 386.3 (M+H, 100); HRMS calcd for C₂₁ H₂₀ N₇ O₁ 386.1729, found 386.1738.

EXAMPLE 112 1-(3-amidinophenyl)-3-methyl-5-([5-(2'-methylsulfonylphenyl)pyrid-2-yl]aminocarbonyl)pyrazole Trifluoroacetate

Part A: Preparation of 2-(tertbutoxycarbonyl)amino-5-bromopyridine and 2-[bis(tertbutoxycarbonyl)amino]-5-bromopyridine

Sodium hydride (1.27 g, 60%, 32 mmol) was added to 2-amino-5-bromopyridine (5.0 g, 29 mmol) in THF (75 mL) at 0° C. The ice bath was removed and the reaction stirred 25 min at room temp. Di-t-butyl dicarbonate (6.94 g, 32 mmol) was added and the reaction was refluxed 15 h. After cooling, the reaction was carefully quenched with water and extracted into EtOAc. The combined organics were washed with sat. NH₄ Cl and sat. NaHCO₃, dried over Na₂ SO₄, filtered, and evaporated. The crude mixture was chromatographed on silica gel (5-7.5% EtOAc/hexanes, followed with 100% CHCl₃) to yield both the mono-protected (2.85 g, 36%) and bis-protected (1.87 g, 17%) products. ¹ HNMR (mono, CDCl₃)δ: 8.32 (d, 1H, J=2.2), 8.13 (bs, 1H), 7.91 (d, 1H, J=8.8 ), 7.75 (dd, 1H, J=8.8, J,=2.2), 1.54 (s, 9H); ¹ HNMR (bis, CDCl₃)δ: 8.53 (d, 1H, J=2.5), 7.84 (dd, 1H, J=8.5, J'=2.5), 7.18 (d, 1H, J=8.4), 1.45 (s, 18H).

Part B: Preparation of 2-[bis(tertbutoxycarbonyl)amino]-5-(2'-methylthiophenyl)pyridine

2-[Bis(tertbutoxycarbonyl)amino]-5-bromopyridine (1.87 g, 5.0 mmol) was dissolved in benzene (120 mL). 2-Methylthiophenylboronic acid (1.95 g, 11.5 mmol), aq. sodium carbonate (12 mL, 2.0 M, 24 mmol), tetrabutyl ammonium bromide (80 mg, 0.25 mmol), and bis(triphenylphosphine)palladium(II)chloride (175 mg, 0.25 mmol) were added, and the resulting mixture was purged with vacuum and argon and then refluxed 16 h. The cooled mixture was diluted with EtOAc and water. The layers were separated, and the organic phase was washed with brine, dried over Na₂ SO₄, filtered, and evaporated. The crude product was chromatographed on silica gel (10-20% EtOAc/hexanes) to yield a thick oil (1.82 g, 87.1%). ¹ HNMR (CDCl₃)δ: 8.51 (d, 1H, J=2.2), 7.83 (dd, 1H, J=8.1, J'=2.2), 7.30 (m, 5H), 2.35 (s, 3H), 1.47 (s, 18H).

Part C: Preparation of 2-[bis(tertbutoxycarbonyl)amino-5-(2'-methylsulfonylphenyl)pyridine

2-[Bis(tertbutoxycarbonyl)amino]-5-(2'-methylthiophenyl)pyridine (1.69 g, 4.1 mmol) was dissolved in MeOH (20 mL). In a separate beaker, a solution of Oxone (10 g) was generated by dilution to 49 mL with water. A portion of this solution (14.5 mL, 4.8 mmol) was removed and adjusted to pH 4 with sat. Na₃ PO₄ solution (4.0 mL). This mixture was added to the reaction and stirred 22 h at room temp. The resulting mixture was diluted with water, extracted with CHCl₃, dried over Na₂ SO₄, filtered, and evaporated. The crude product was chromatographed on silica gel (40-75% EtOAc/hexanes) to yield the sulfone (1.19 g, 65%). ¹ HNMR (CDCl₃)δ: 8.48 (d, 1H, J=1.8), 8.26 (dd, 1H, J=8.1, J'=1.5), 7.95 (dd, 1H, J=8.1, J'=2.2), 7.71 (td, 1H, J=7.4, J'=1.5), 7.64 (td, 1H, J=7.7, J'=1.4), 7.40 (dd, 1H, J=7.3, J'=1.4), 7.36 (d, 1H, J=8.8), 2.68 (s, 3H), 1.48 (s, 18H).

Part D: Preparation of 2-amino-5-(2'-methylsulfonylphenyl)pyridine hydrochloride

2-[Bis(tertbutoxycarbonyl)amino-5-(2'-methylsulfonylphenyl)pyridine (1.18 g, 2.6 mmol) and 2-(tertbutoxycarbonyl)amino-5-(2'-methylsulfonylphenyl)pyridine (1.62 g, 4.6 mmol) were suspended in HCl/dioxane (30 mL, 4.0 M) and stirred 23 h at room temp. The resulting mixture was diluted with Et₂ O and filtered to yield a tan solid (2.27 g, 100%). ¹ HNMR (DMSO)δ: 8.09 (m, 3H), 7.98 (d, 1H, J=1.8), 7.90 (dd, 1H, J=9.1, J'=2.2), 7.75 (m, 2H), 7.45 (dd, 1H, J=7.3, J'=1.1), 6.98 (d, 1H, J==9.1), 3.04 (s, 3H).

Part E: Preparation of l-(3-cyanophenyl)-3-methyl-5-([5-(2'-methylsulfonylphenyl)pyrid-2-yl]aminocarbonyl)pyrazole

Oxalyl chloride (175 μl, 2.0 mmol) and DMF (2 drops) were added to 1-(3-cyanophenyl)-3-methylpyrazole-5-carboxylic acid (300 mg, 1.3 mmol) in CH₂ Cl₂ (5 mL) and stirred under argon 160 min. The resulting solution was evaporated and redissolved in CH₂ Cl₂ (5 mL). 4-Dimethylaminopyridine (484 mg, 4.0 mmol) and 2-amino-5-(2'-methylsulfonylphenyl)pyridine hydrochloride (376 mg, 1.3 mmol) were added and stirred at room temperature under argon for days. The reaction was evaporated and chromatographed on silica gel (50-100% EtOAc/hexanes, followed by 1% MeOH/EtOAc) to yield the desired product (303 mg, 50%). ¹ HNMR (CDCl₃)δ: 8.54 (s, 1H), 8.39 (d, 1H, J=2.2), 8.25 (d, 2H, J=8.4), 7.82 (m, 2H), 7.66 (m, 5H), 7.37 (dd, 1H, J=7.7, J'=1.5), 6.76 (s, 1H), 2.75 (s, 3H), 2.41 (s, 3H).

Part F: Preparation of 1-(3-amidinophenyl)-3-methyl-5-([5-(2'-methylsulfonylphenyl)pyrid-2-yl]aminocarbonyl)pyrazole Trifluoroacetate

1-(3-cyanophenyl)-3-methyl-5-([5-(2'-methylsulfonylphenyl)pyrid-2-yl]aminocarbonyl)pyrazole (300 mg, 0.66 mmol) was dissolved in dry CHCl₃ (15 mL) and dry MeOH (5 mL) and cooled to 0° C. HCl (g) was generated by the addition of H₂ SO₄ (45 mL) to NaCl (200 g) over 90 min, and bubbled into the reaction. The generator was removed, and the reaction was sealed and placed in the refrigerator (4° C.) overnight. The reaction was evaporated and redissolved in dry MeOH (10 mL). Ammonium carbonate (316 mg, 3.3 mmol) was added and the reaction was stirred 20 h at room temp, and evaporated. The crude product was purified by prep HPLC on a C-18 reverse phase column (10-70% MeCN/H₂ O/0.05% TFA) to yield a white powder (161 mg, 42%). ¹ HNMR (DMSO)δ: 11.21 (s, 1H), 9.38 (s, 2H), 8.96 (s, 2H), 8.36 (s, 1H), 8.07 (d, 1H, J=7.3), 7.99 (d, 1H, J=8.5), 7.92 (s, 1H), 7.73 (m, 6H), 7.42 (d, 1H, J=7.7), 7.16 (s, 1H), 2.92 (s, 3H), 2.29 (s, 3H). HRMS calc. for C₂₄ H₂₃ N₆ O₃ S: 475.1552; found, 475.1554.

EXAMPLES 113, 114, AND 115 1-(3-amidinophenyl)-3-methyl-5-([5-(2'-methylsulfonylphenyl)pyrimid-2-yl]aminocarbonyl)pyrazole Trifluoroacetate, (Example 113) 1-(3-cyanophenyl)-3-methyl-5-([5-(2'-methylsulfonylphenyl)pyrimid-2-yl]aminocarbonyl)pyrazole, (Example 114) and 1-(3-aminocarbonylphenyl)-3-methyl-5-([5-(2'-methylsulfonylphenyl)pyrimid-2-yl]aminocarbonyl)pyrazole (Example 115)

Part A: Preparation of 2-methylthiophenylboronic Acid

2-Bromothioanisole (29.0 g, 143 mmol) was dissolved in dry THF (400 mL) and cooled to -75° C. N-BuLi (62.0 mL, 2.5 M in hexane, 155 mmol) was added over 50 min. After stirring 25 min, triisopropyl borate (46 mL, 199 mmol) was added over 35 min. The cold bath was removed and the reaction was stirred at room temperature for 16 h. The resulting solution was cooled in an ice bath, and 6 M HCl (100 mL) was added. This mixture was stirred at room temp 5 h and concentrated to about half of the original volume. The concentrated solution was partitioned between Et₂ O and water. The organic layer was extracted with 2 M NaOH, which was subsequently reacidified with 6 M HCl and extracted several times back into Et₂ O. These Et₂ O washes were dried over Na₂ SO₄, filtered, and evaporated to yield a beige solid (20.4 g, 85%). ¹ HNMR (CDCl₃) δ: 8.01 (dd, 1H, J=7.3, J-=1.4), 7.53 (dd, 1H, J=7.7, J'=1.1), 7.43 (td, 1H, J=7.3, J'=1.8), 7.34 (td, 1H, J=7.3, J'=1.5), 6.22 (s, 2H), 2.50 (s, 3H).

Part B: Preparation of 2-[bis(tert-butoxycarbonyl)amino]-5-bromopyrimidine

Sodium hydride (5.06 g, 60%, 127 mmol) was added in 2 portions to 2-amino-5-bromopyrimidine (10.0 g, 57 mmol) in dry THF (500 mL) at 0° C. After stirring 30 min, di-t-butyl dicarbonate (27.6 g, 126 mmol) was added. The resulting mixture was refluxed 17 h, quenched carefully with water, and concentrated. The concentrated mixture was diluted with EtOAc and extracted with water. The combined aqueous layers were extracted with EtOAc. All of the organic layers were combined, dried over Na₂ SO₄, filtered, and evaporated. The crude product was chromatographed on silica gel (10-15% EtOAc/hexanes) to yield the desired product (15.48 g, 72%). ¹ HNMR (CDCl₃) δ: 8.78 (s, 2H), 1.47 (s, 18H).

Part C: Preparation of 2-[bis(tert-butoxycarbonyl)amino]-5-(2'-methylthiophenyl)pyrimidine

2-[Bis(tert-butoxycarbonyl)amino]-5-bromopyrimidine (2.00 g, 5.3 mmol) was dissolved in benzene (130 mL). 2-methylthiophenylboronic acid (2.24 g, 13.3 mmol), aq. sodium carbonate (13 mL, 2.0 M, 26 mmol), tetrabutyl ammonium bromide (86 mg, 0.26 mmol), and bis(triphenylphosphine)palladium(II)chloride (190 mg, 0.27 mmol) were added, and the resulting mixture was purged with vacuum and argon and then refluxed 17 h. The cooled mixture was diluted with EtOAc and water. The layers were separated, and the organics were dried over Na₂ SO₄, filtered, and evaporated. The crude product was chromatographed on silica gel (50% EtOAc/hexanes), evaporated, and chromatographed a second time on silica gel (30-50% EtOAc/hexanes) to yield the desired product (2.13 g, 96%). ¹ HNMR (CDCl₃)δ: 8.81 (s, 2H), 7.41 (m, 2H), 7.25 (m, 2H), 2.39 (s, 3H), 1.49 (s, 18H).

Part D: Preparation of 2-[bis(tert-butoxycarbonyl)amino]-5-(2'-methylsulfonylphenyl)pyrimidine

2-[Bis(tertbutoxycarbonyl)amino]-5-(2'-methylthiophenyl)pyrimidine (2.13 g, 5.1 mmol) was dissolved in MeOH (20 mL) and cooled to 0° C. In a separate beaker, a solution of Oxone (5.49 g) was generated by dilution to 27 mL with water. A portion of this solution (17 mL, 5.6 mmol) was removed and adjusted to pH 4.2 with sat. Na₃ PO₄ solution (4.7 mL). This mixture was added to the reaction and stirred 23 h at room temp. The resulting mixture was diluted with water and extracted with CHCl₃. The organics were combined, washed with water and brine, dried over Na₂ SO₄, filtered, and evaporated. The crude product was chromatographed on silica gel (50-100% EtOAc/hexanes) to yield the sulfone (1.28 g, 56%). ¹ HNMR (CDCl₃) δ: 8.81 (s, 2H), 8.28 (dd, 1H, J=7.6, J'=1.4), 7.72 (m, 2H), 7.39 (dd, 1H, J=7.3, J'=1.4), 2.76 (s, 3H), 1.50 (s, 18H).

Part E: Preparation of 2-amino-5-(2'-methylsulfonylphenyl)pyrimidine hydrochloride

2-[Bis(tertbutoxycarbonyl)amino]-5-(2'-methylsulfonylphenyl)pyrimidine (1.28 g, 2.8 mmol) was suspended in HCl/dioxane (10 mL, 4.0 M) and stirred 20 h at room temp. The resulting mixture was triturated with Et₂ O and filtered to yield a white solid (772 mg, 95%). ¹ HNMR (CDCl₃ +few drops MeOD) δ: 8.53 (s, 2H), 8.22 (dd, 1H, J=7.7, J'=1.8), 7.77 (m, 2H), 7.40 (dd, 1H, J=7.4, J'=1.5), 2.94 (s, 3H).

Part F: Preparation of 1-(3-cyanophenyl)-3-methyl-5-([5-(2'-methylsulfonylphenyl)pyrimid-2-yl]aminocarbonyl)pyrazole

Oxalyl chloride (175 μl, 2.0 mmol) and DMF (2 drops) were added to 1-(3-cyanophenyl)-3-methylpyrazole-5-carboxylic acid (300 mg, 1.3 mmol) in CH₂ Cl₂ (5 mL) and stirred under argon for 120 min. The resulting solution was evaporated and redissolved in CH₂ Cl₂ (5 mL). 4-Dimethylaminopyridine (480 mg, 3.9 mmol) and 2-amino-5-(2'-methylsulfonylphenyl)pyrimidine hydrochloride (377 mg, 1.3 mmol) were added and stirred at room temp under argon 5 days. The crude reaction was chromatographed on silica gel (2-5% MeOH/CHCl₃) to yield crude product, which was redissolved in CHCl₃ and extracted with 1 M HCl. The organics were dried over Na₂ SO₄, filtered, and evaporated to yield clean product (486 mg, 80%). ¹ HNMR (CDCl₃)δ: 8.69 (s, 2H), 8.64 (s, 1H), 8.25 (dd, 1H, J=7.7, J'=1.5), 7.84 (m, 1H), 7.73 (m, 4H), 7.55 (t, 1H, J=7.6), 7.35 (dd, 1H, J=7.3, J'=1.4), 6.79 (s, 1H), 2.80 (s, 3H), 2.42 (s, 3H).

Part G: Preparation of 1-(3-amidinophenyl)-3-methyl-5-([5-(2'-methylsulfonylphenyl)pyrimid-2-yl]aminocarbonyl)pyrazole Trifluoroacetate, and 1-(3-aminocarbonylphenyl)-3-methyl-5-([5-(2'-methylsulfonylphenyl)pyrimid-2-yl]aminocarbonyl)pyrazole

1-(3-cyanophenyl)-3-methyl-5-([5-(2'-methylsulfonylphenyl)pyrimid-2-yl]aminocarbonyl)pyrazole (471 mg, 1.0 mmol) was dissolved in dry CHCl₃ (15 mL) and dry MeOH (5 mL) and cooled to 0° C. HCl (g) was generated by the addition of H₂ SO₄ (45 mL) to NaCl (480 g) over 30 min, and bubbled into the reaction. The generator was removed, and the reaction was sealed and placed in the refrigerator (4° C.) for 18 h. The reaction was evaporated and redissolved in dry MeOH (15 mL). Ammonium carbonate (487 mg, 5.1 mmol) was added and the reaction was stirred for 20 h at room temp, and evaporated. The crude product was dissolved/suspended in a mixture of MeCN, water, TFA, DMSO, and MeOH. The soluble portion was purified by prep HPLC on a C-18 reverse phase column (10-70% MeCN/H₂ O/0.05% TFA) to yield the desired amidine as its TFA salt (0.31 g, 51%). ¹ HNMR (DMSO)δ: 11.38 (s, 1H), 9.39 (s, 2H), 9.00 (s, 2H), 8.67 (s, 2H), 8.10 (dd, 1H, J=8.1, J'=1.5), 7.92 (m, 1H), 7.74 (m, 5H), 7.49 (dd, 1H, J=7.3, J'=1.1), 7.06 (s, 1H), 3.03 (s, 3H), 2.29 (s, 3H). HRMS calc. for C₂₃ H₂₂ N₇ O₃ S: 476.1505; found, 476.1529. A second product was isolated from the prep HPLC and combined with the insoluble solid from above for purification on silica gel (10% MeOH/CHCl₃). The crude amide was suspended in toluene and filtered. The white solid thus obtained was the desired amide (52 mg, 11%). ¹ HNMR(DMSO) δ: 11.33 (s, 1H), 8.64 (s, 2H), 8.08 (m, 2H), 7.92 (s, 1H), 7.77 (m, 3H), 7.48 (m, 4H), 6.95 (s, 1H), 3.01 (s, 3H), 2.27 (s, 3H). HRMS calc. for C₂₃ H₂₁ N₆ O₄ S: 477.1345; found, 477.1350.

EXAMPLE 116 1-(3-(N-aminoamidino)phenyl)-3-methyl-5-[(2'-tert-butylaminosulfonyl-[1,1']-biphen-4-yl) aminocarbonyl]pyrazole, Trifluoroacetic Acid Salt

1-(3-Cyanophenyl)-3-methyl-5-[(2'-tert-butylaminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole (150 mg) was dissolved in anhydrous CH₃ OH and cooled to 0° C. Anhydrous HCl was bubbled through the rxn for 15 minutes. The resulting solution was allowed to warm to rt over 18 hrs. The mixture was concentrated in vacuo . LRMS (M+H)+=489 C₂₅ H₂₃ N₅ O₄ S₁. 50 mg was dissolved in 10 mL of anhydrous CH₃ OH. Hydrazine (0.10 mL) was added and the resulting mixture was stirred at rt for 4 hours. The mixture was concentrated under vacuo. Purification was done by HPLC yielding 2.5 mg (98% purity by HPLC). HRMS for C₂₈ H₃₁ N₇ O₃ S₁ (M+H)⁺ calc. 490.162947, found 490.164868. ¹ HNMR (CD₃ OD)S: δ: 1.02 (s, 9H), 2.38 (s, 3H), 6.94 (s, 1H), 7.305 (d, 1H, J=7.69 Hz), 7.53 (t, 1H, 7.69 Hz), 6.64-7.85 (m 7H), 8.085 (d, 1H, J=8.06 Hz).

EXAMPLE 117 1-(3-(N-aminoamidino)phenyl)-3-methyl-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole, Trifluoroacetic Acid Salt

3-[4-(2-(N-butylaminosulfonyl)phenyl)aminophenyl-3-methyl-5-carboxypyrazole]cyanophenyl (1.0 g) was dissolved in anhydrous CH₃ OH and cooled to 0° C. Anhydrous HCl was bubbled through the rxn for 15 minutes. The resulting solution was allowed to warm to rt over 18 hrs. The mixture was concentrated in vacuo . LRMS (M+H)+=489 C₂₅ H₂₃ N₅ O₄ S₁. 300 mg was dissolved in 10 mL of anhydrous CH₃ OH. Hydrazine (0.023 mL) was added and the resulting mixture was stirred at rt for 4 hours. The mixture was concentrated under vacuum. Purification was done by HPLC yielding 23 mg (98%. purity by HPLC). HRMS for C₂₄ H₂₃ N₇ O₃ S₁ (M+H)+calc. 546.228735, found 546.228088. ¹ HNMR (CD₃ OD)δ: 2.38 (s, 3H), 6.94, (s, 1H), 7.31 (d, 1H, J=7.33 Hz), 7.495 (d, 2H, J=7.33 Hz), 7.59-7.86 (m, 7H), 8.08 (d, 1H, J=7.69 Hz).

EXAMPLE 118 1-(3-(N-methyl-N-hydroxyaamidino)phenyl)-3-methyl-5-[(2'-t-butylaminosulfonyl-[1,1']-biphen-4-yl) aminocarbonyl]pyrazole, Trifluoroacetic Acid Salt

3-[4-(2-(t-butylaminosufonyl)phenyl)amino phenyl-3-methyl-5-carboxypyrazole]cyanophenyl (300 mg) was dissolved/suspended in 25 mL of CH₃ OH. Triethylamine (0.098 mL) added along with N,N-methylhydroxylamine hydrochloride (0.048 g). The reaction was stirred at 50° C. for 15 hours. The mixture was concentrated under vacuo. Purification was done on silica gel using 10% CH₃ OH/CH2Cl2 as the eluent yielding 360 mg. HRMS for C₂₉ H₃₂ N₆ O₄ S₁ (M+H)+calc. 561.228401, found 561.22987. ¹ HNMR (CD₃ OD)δ: 1.02 (s, 9H), 2.38 (s, 3H), 3.40 (s, 3H), 3.62 (s, 1H), 6.96 (s, 1H), 7.305 (d, 1H, J=7.69 Hz), 7.42 (d, 2H, J=8.79 Hz), 3.53 (t, 1H, J=8.06 Hz), 7.60 (t, 1H, J=7.32 Hz), 7.65 (d, 2H, J=8.06 Hz), 7.70-7.78 (m, 4H), 8.085 (d, 1H, J=7.69 Hz).

EXAMPLE 119 1-(3-(N-methylamidino)phenyl)-3-methyl-5-[(2'-tert-butylaminosulfonyl-[1,1'-biphen-4-yl)aminocarbonyl]pyrazole, Trifluoroacetic Acid Salt

1-(3-(N-Methyl-N-hydroxy-amidino)phenyl)-3-methyl-5-[(2'-n-butylaminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole (300 mg) was dissolved in acetic acid (25 mL). Trifluoroacetic anhydride (0.106 mL) was added and the reaction was stirred at rt for 35 minutes. 10% Pd/C (300 mg) was added and the reaction vessel was placed on the Parr Shaker (50 psi H₂) for 17 hours. The reaction was filtered through C-lite and the mixture was concentrated under vacuum. Purification was done by HPLC yielding 33 mg (97% purity by HPLC). HRMS for C₂₉ H₃₂ N₆ O₃ S₁ (M+H)+calc. 545.233486, found 545.233079; ¹ HNMR(CD₃ OD)δ: 1.02 (s, 9H), 2.38 (s, 3H), 3.09 (s, 3H), 6.94 (s, 1H), 7.30 (d, 1H, J=7.33 Hz), 7.425 (d, 2H, J=8.42 Hz) 7.50 (t, 1H, J=7.69 Hz), 7.57-7.64 (m, 3H), 7.685 (d, 1H, J=7.32 Hz), 7.73-7.77 (m, 2H), 7.87 (s, 1H), 8.085 (d, 1H, J=7.70 Hz).

EXAMPLE 120 1-(3-(N-methylamidino)phenyl)-3-methyl-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole, Trifluoroacetic Acid Salt

1-(3'-(N-Methyl-N-hydroxy-amidino)phenyl)-3-methyl-5-[(2'-n-butylaminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole (347 mg) was dissolved in trifluoroacetic acid (10 mL) and stirred at 50° C. for 1 hour. The mixture was concentrated in vacuo (346 mg). LRMS for C₂₅ H₂₄ N₆ O₄ S₁ (M+H)⁺ =505. This material (346 mg) was dissolved in acetic acid (100 mL). Trifluoroacetic anhydride (0.116 mL) was added and the reaction was stirred at rt for 35 minutes. 10% Pd/C (300 mg) was added and the rxn was placed on the Parr shaker (50 psi H2) for 18 hours. The reaction was filtered through Celite and the mixture was concentrated in vacuo. Purification was done by HPLC yielding 80 mg (98% purity by HPLC). HRMS for C₂₅ H₂₄ N₆ O₃ S₁ (M+H)+calc. 489.172971, found 489.172971; ¹ HNMR (CD₃ OD) δ: 2.38 (s, 3H), 3.08 (s, 3H), 6.94 (s, 1H), 7.31 (d, 1H, J=7.33 Hz), 7.395 (d, 2H, J=8.79 Hz) 7.51 (t, 1H, J=7.32 Hz), 7.57-7.68 (m, 6H), 8.085 (d, 1H, J=7.47 Hz).

EXAMPLE 121 1-(3-amidinophenyl)-5-[(2'-aminosulfonylphenyl)pyridin-2-yl]aminocarbonyl]tetrazole, Trifluoroacetic Acid Salt

The title compound was prepared as colorless crystals following the standard Pinner amidine reaction sequence and purification protocols outlined previously (Example 24); ¹ HNMR (DMSO) δ:8.40-6.95 (m, 11H); 9.25 (s, 1H); 9.50 (s, 1H); 11.55 (s, 1H). MS (ESI) 464.17 (M+H)⁺.

EXAMPLE 122 1-(3-aminocarbonylphenyl)-5-{[5-(2'-aminosulfonylphenyl)pyridin-2-yl]aminocarbonyl}tetrazole

The title compound was prepared as colorless crystals following the standard Pinner followed by hydrolysis and purification protocols outlined previously; ¹ HNMR(DMSO) δ: 8.40-7.39 (m, 11H); 11.55 (s, 1H). MS (ESI) 465.11 (M+H)⁺.

EXAMPLE 123 1-(3-amidinophenyl)-5-{[5-(2'-trifluoromethylphen-1-yl)pyridin-2-yl]aminocarbonyl}tetrazole, Trifluoroacetic Acid Salt

The title compound was prepared as colorless crystals following the standard Pinner amidine reaction sequence and purification protocols outlined previously; ¹ HNMR (DMSO) δ: 8.40-7.49 (m, 11H); 9.25 (s, 1H); 9.5 (s, 1H); 11.60 (s, 1H); MS (ESI) 453.20 (M+H)⁺.

EXAMPLE 124 1-(3-amidinophenyl)-5-[(4'-bromophen-1-yl) Aminocarbonyl]tetrazole, Trifluoroacetic Acid Salt

The title compound was prepared as colorless crystals following the standard Pinner amidine reaction sequence and purification protocols outlined previously; ¹ HNMR (DMSO) δ: 8.20-7.55 (m, 8H); 9.20 (s, 1H); 9.5 (s, 1H); 11.55 (s, 1H); MS (ESI) 386.03 (M+H)⁺.

EXAMPLE 125 1-(3-aminocarbonylphenyl)-5-{[5-(2'-trifluoromethylphen-1-yl)pyridin-2-yl]aminocarbonyl}tetrazole

The title compound was prepared as colorless crystals following the standard Pinner followed by hydrolysis reaction sequence and purification protocols outlined previously; ¹ HNMR(DMSO) δ:8.40-7.50 (m, 11H); 11.60 (s, 1H). MS (ESI) 454.12 (M+H)⁺.

EXAMPLE 126 5-(3-amidinophenyl)-1-[(2'-trifluoromethyl-[1,1']-biphen-4-yl)methyl]tetrazole, Trifluoroacetic Acid Salt

Part A. Preparation of N-(4-bromophenylmethyl)-3-cyanobenzamide

4-Bromobenzylamine HCl (3.36 g, 15.1 mmol) was dissolved in CH₂ Cl₂ (100 mL). Triethylamine (8.4 mL, 60 mmol) was added followed by 3-cyanobenzyl chloride (2.50 g, 15.1 mmol). The mixture was stirred at room temperature under N₂ for 15 min. It was diluted with CH₂ Cl₂ and washed with water and brine. The CH₂ Cl₂ solution was dried over MgSO₄ and concentrated to 3.5 g of the desired product. ¹ HNMR (CDCl₃) δ: 4.60 (d, 2H); 7.0 (s, 1H); 7.20 to 8.20 (m, 8H). MS (DCI-NH₃) 315 (M+H)⁺.

Part B. Preparation of 1-(4-bromophenylmethyl)-5-(3-cyanophenyl)tetrazole

The material from Part A (3.2 g, 10 mmol) was dissolved in CH₃ CN (100 mL) and NaN₃ (0.7 g, 10 mmol) was added. The mixture was cooled in an ice bath and triflic anhydride (1.7 mL, 10 mmol) was added. Then, the ice bath was removed and stirred at room temperature under N₂ overnight. The reaction mixture was diluted with EtOAc and washed with water and brine. It was dried over MgSO₄, concentrated, and chromatographed on silica gel (CH₂ Cl₂) to give 2.0 g of the desired product. ¹ HNMR (CDCl₃) δ: 5.60 (s, 2H); 7.05 to 7.90 (m, 8H). MS (NH₃ -CI) 340, 342 (M+H)⁺.

Part C. Preparation of 5-(3-cyanophenyl)-1-[(2'-trifluoromethyl-[1,1']-biphen-4-yl)methyl]tetrazole

The material from Part B (0.36 g, 1.06 mmol), and 2-trifluoromethyl phenylboronic acid (0.24 g, 1.26 mmol) were dissolved in benzene (30 mL). The mixture was stirred at room temperature and bubble N₂ for 30 min. Then K₂ CO₃ (2 mL of 2 M, 4 mmol), tetrabutylammonium bromide (50 mg, 0.15 mmol) and tetrakis(triphenylphosphine)-palladium(0) (200 mg, 0.17 mmol) were added. The mixture was refluxed under N₂ for 4 hours. The solvent was removed. The residue was dissolved in CH₂ Cl₂ and washed with water and brine. It was dried over MgSO₄, concentrated, and chromatographed on silica gel (eluted with CH₂ Cl₂) to give 0.41 g of the desired product. ¹ HNMR (CDCl₃) δ: 5.70 (s, 2H); 7.10 to 7.85 (m, 12H). MS (NH₃ -CI) 406.1 (M+H)⁺.

Part D. Preparation of 5-(3-amidinophenyl)-1-[(2'-trifluoromethyl-[1,1']-biphen-4-yl)methyl]tetrazole, Trifluoroacetic Acid Salt

The material from part C was dissolved in 10 mL anhydrous CHCl₃ and 10 mL anhydrous CH₃ OH. The mixture was cooled in an ice bath and HCl gas was bubbled in until the solution was saturated. The reaction mixture was sealed and kept at 0° C. for 12 h. The solvent was removed and the solid was dried under vacuum. The resulting solid was redissolved in 20 mL of anhydrous CH₃ OH and ammonium acetate (0.77 g, 10 eq) was added. The mixture was sealed and stirred at room temperature for 12 h. The solvent was removed. The solid was dissolved in CH₃ CN/H₂ O/TFA and purified by reverse phase HPLC to give 150.0 mg of the desired product. ¹ HNMR (DMSO-d6) δ: 5.95 (s, 1H); 7.19 to 8.20 (m, 12H); 9.35 (s, 1H); 9.50 (s, 1H). (ESI) 423.17 (M+H)⁺.

EXAMPLE 127 1-[(3-amidinophenyl)methyl]-3-methyl-5-[(2'-aminosulfonyl-[1,1']-1-biphen-4-yl)aminocarbonyl]pyrazole, Trifluoroacetic Acid Salt

Part A. Preparation of ethyl 1-[(3-cyanophenyl)methyl]-3-methylpyrazole-5-carboxylate

To a solution of ethyl 3-methylpyrazole-5-carboxylate (2.0 g, 13.0 mmol) in 50 mL of dimethylformamide was added 3-cyanobenzyl bromide (2.54 g, 13.0 mmol) and potassium iodide (6.46 g, 38.9 mmol). The resulting mixture was allowed to stir at 65° C. for 16 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with saturated aq. sodium thiosulfate (2 times) and brine (2 times), dried (MgSO4) and concentrated in vacuo . The residue was purified by flash chromatography (elution with 1:1 hexanes/ethyl acetate) to give 2.5 g (71%) of the title compound. MS (ESI) 270 (M+H)+.

Part B. Preparation of 1-[(3-cyanophenyl)methyl]-3-methylpyrazole-5-carboxylate

To a solution of ethyl 1-[(3-cyanophenyl)methyl]-3-methylpyrazole-5-carboxylate (2.37 g, 8.80 mmol) in 20 mL of methanol and 20 mL of water was added sodium hydroxide (0.70 g, 17.6 mmol) and the resulting solution was stirred at room temperature for 16 h. The mixture was acidified with 10% aq HCl, diluted with ethyl acetate, washed with brine (2 times), dried (MgSO₄) and concentrated in vacuo to afford the title compound (1.9 g, 90%) which was used without purification. MS (ESI) 242 (M+H)+.

Part C. Preparation of 1-[(3-cyanophenyl)methyl]-3-methyl-5-[(2'-tert-butylaminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole

To a solution of 1-[(3-cyanophenyl)methyl]-3-methylpyrazole-5-carboxylate (1.80 g, 7.46 mmol) in 20 mL of dimethylformamide was added (2'-tert-butylaminosulfonyl-[1,1']-biphen-4-yl)amine (2.50 g, 8.21 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent, 4.95 g, 11.19 mmol) and triethylamine (1.13 g, 11.19 mmol). The resulting mixture was stirred at 60° C. for 16 h. The reaction was allowed to cool to room temperature and then was diluted with ethyl acetate, washed with brine (4 times), dried (MgSO₄) and concentrated in vacuo. The residue was purified by flash chromatography (elution with 1:1 hexanes/ethyl acetate) to afford 1.9 g (49%) of the title compound. MS (ESI) 528 (M+H)+.

Part D. Preparation of 1-[(3-amidinophenyl)methyl]-3-methyl-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole, Trifluoroacetic Acid Salt

To a solution of 1-[(3-cyanophenyl)methyl]-3-methyl-5-[(2'-tert-butylaminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole (1.77 g, 3.35 mmol) in 40 mL of methyl acetate was added anhydrous methanol (1.36 mL, 33.5 mmol). The solution was cooled to 0° C. Then anhydrous HCl was bubbled through the solution for 15 minutes. The solution was stoppered and allowed to stir overnight at room temperature. The volatiles were removed in vacuo. The residue was dried under high vacuum for 1 hr. The residue was then dissolved in 100 mL of anhydrous methanol. Ammonium carbonate (1.93 g, 20.21 mmol) was added and the reaction was stirred overnight at room temperature. The volatiles were removed in vacuo and the residue was purified by preparative HPLC (C18 reverse phase column, elution with a H₂ O/CH₃ CN gradient with 0.5% TFA) to yield the title compound as a white powder. MS (ESI) 489 (M+H)⁺.

EXAMPLE 128 1-[(4-Amidinophenyl)methyl]-3-methyl-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole, Trifluoroacetic Acid Salt

Part A. Preparation of ethyl 1-[(4-cyanophenyl)methyl]-3-methylpyrazole-5-carboxylate

Ethyl-3-methylpyrazole-5-carboxylate (2.50 g, 16.21 mmol) was allowed to react with 4-cyanobenzyl bromide (3.18 g, 16.21 mmol) and potassium iodide (8.07 g, 48.65 mmol) to afford 3.1 g (70%) of the title compound. MS (ESI) 270 (M+H)+.

Part B. Preparation of 5-carboxy-1-[(4-cyanophenyl)methyl]-3-methylpyrazole

Ethyl-1-[(4-cyanophenyl)methyl]-3-methylpyrazole-5-carboxylate (2.96 g, 10.99 mmol) was converted into 2.4 g (91%) of the title compound following the procedure outlined previously; MS (ESI) 242 (M+H)+.

Part C. Preparation of 1-[(4-cyanophenyl)methyl]-3-methyl-5-[(2'-tert-butylaminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole

5-carboxy-1-[(4-cyanophenyl)methyl]-3-methylpyrazole-5-carboxylate (2.29 g, 9.49 mmol) was converted into 2.0 g (40%) of the title compound following the procedure outlined previously; MS (ESI) 528 (M+H)+.

Part D. Preparation of 1-[(4-amidinophenyl)methyl]-3-methyl-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole, Trifluoroacetic Acid Salt

1-[(4-cyanophenyl)methyl]-3-methyl-5-[(2'-tert-butylaminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole (0.78 g, 1.47 mmol) was converted into the title compound following methods described previously; MS (ESI) 489 (M+H)⁺.

EXAMPLE 129 1-(3-amidinophenyl)-2-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]imidazole, Trifluoroacetic Acid Salt

Part A: 3-Fluorobenzonitrile (4.84 g, 40 mmol) was heated with imidazole (2.72 g, 40 mmol) in the presence of K₂ CO₃ in DMF at 100° C. for 8 hours to afford the coupled product as a white solid in quantitative yield. ¹ HNMR (CDCl₃) δ: 7.89 (s, 1H), 7.70 (d, J=0.8 Hz, 1H), 7.68-7.58 (m, 3H), 7.30 (d, J=1.0 Hz, 1H), 7.26 (s, 1H); LRMS: 170 (M+H)⁺.

Part B: Product from part A (1.52 g, 9 mmol) was slowly treated with n-BuLi (1.6 M, 6.3 mL) in THF (60 mL) at -78° C. for 40 minutes and was then slowly quenched with chloromethylformate (942 mg, 10 mmol) at this temperature. The resulting mixture was stirred at -78° C. and warmed to room temperature over 2 hours. Then poured into water and ethyl acetate. The organic layer was separated and washed with water, brine, and dried over MgSO₄. After removal of the ethyl acetate, a residue was purified by column chromatography with ethyl acetate and methylene chloride (1:1) to afford the 2-imidazolylphenylethylester derivative (1.33 g, 65%) as a white solid. ¹ HNMR (CDCl₃)δ: 7.80-7.77 (m, 1H), 7.65-7.61 (m, 3H), 7.33 (s, 1H), 7.20 (s, 1H); LRMS: 228 (M+H)⁺.

Part C To a stirred solution of 4-[(o-SO₂ tBu)-phenyl]aniline (304 mg, 1 mmol) in CH₂ Cl₂ (20 mL) was slowly added trimethylaluminum (2M in hexane, 1 mL) at 0° C. and the resulting mixture was warmed to room temperature over 15 minutes. The product from part B in CH₂ Cl₂ (5 mL) was added dropwise and the resulting mixture was refluxed for 2 hours. The mixture was quenched with water, diluted with ethyl acetate and filtered through Celite. The organic layer was separated, washed with water, brine and dried over MgSO₄. After removal of the ethyl acetate, a residue was purified by column chromatography with ethyl acetate and methylene chloride (1:1) as eluent to afford the coupled product (260 mg, 52%) as a white solid. ¹ HNMR (CDCl₃)δ: 9.41 (s, 1H), 8.15 (dd, J=7.7 Hz, J=1.5 Hz, 1H), 7.78 (dd, J=7.3 Hz, J=1.1 Hz, 1H), 7.74-7.57 (m, 6H), 7.55 (td, J=7.7 Hz, J=1.1 Hz, 1H), 7.49 (dd, J=8.8 Hz, J=1.8 Hz, 2H), 7.29 (dd, J=8.1 Hz, J=1.5 Hz, 1H), 7.28 (d, J=0.8 Hz, 1H), 7.22 (d, J=0.8 Hz, 1H), 3.64 (s, 1H), 0.99 (s, 9H); LRMS: 500.1 (M+H)⁺.

Part D: Standard Pinner amidine and purification methods then afforded the titled product (120 mg, 50%): ¹ HNMR (CD₃ OD) δ: 8.08 (dd, J=7.7 Hz, J=1.1 Hz, 1H), 7.91-7.88 (m, 2H), 7.83 (dd, J=8.4 Hz, J=1.5 Hz, 1H), 7.74 (t, J=8.0 Hz, 1H), 7.65 (d, J=8.4 Hz, 2H), 7.58 (dd, J=7.3 Hz, J=1.1 Hz, 1H), 7.50 (s, 2H), 7.39 (d, J=8.4 Hz, 2H), 7.32 (s, 1H), 7.30 (dd, J=7.3 Hz, J=1.1 Hz, 1H); ESMS: 461 (M+H)⁺.

EXAMPLE 130 1-(3-amidinophenyl)-4-methyl-2-[(2'-aminosulfonyl-[1,1']-biphen-4-yl) aminocarbonyl]imidazole

Ethyl-1-(3-cyanophenyl)-4-methyl-imidazolyl-2-carboxylate was prepared following the standard coupling procedure outlined previously. This was coupled following the standard Weinreb conditions (trimethylaluminum) and subjected to the Pinner amidine reaction protocols followed by usual methods of purification to afford the title compound as colorless crystals. ¹ HNMR (CD₃ OD)δ: 8.09 (dd, J=8.1 Hz, J=1.1 Hz, 1H), 7.89 (t, J=1.5 Hz, 1H), 7.87 (d, J=1.8 Hz, 1H), 7.81-7.78 (m, 1H), 7.72 (t, J=8.1 Hz, 1H), 7.64 (d, J=8.4 Hz, 2H), 7.57 (dd, J=7.7 Hz, J=1.5 Hz, 1H), 7.50 (td, J=7.7 Hz, J=1.5 Hz, 1H), 7.38 (d, J=8.4 Hz, 2H), 7.30 (dd, J=7.7 Hz, J=1.5 Hz, 1H), 7.26 (s, 1H), 2.33 (s, 3H); ¹³ C NMR (CD₃ OD)δ: 167.73, 158.04, 143.04, 141.49, 140.47, 139.62, 138.64, 137.53, 133.65, 133.45, 132.93, 132.76, 132.35, 131.25, 130.55, 129.09, 128.74, 128.63, 126.69, 120.87, 13.27; ESMS: m/z 475.19 (M+H, 100); HRMS: calcd. for C₂₄ H₂₃ N₆ O₃ S₁ 475.1552 found 475.1548.

EXAMPLE 131 1-(3-amidinophenyl)-5-chloro-4-methyl-2-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]imidazole

Chlorination of ethyl-1-(3-cyanophenyl)-4-methyl-imidazole-2-carboxylate with NCS in refluxing carbontetrachloride afforded the 5-chloroimidazole derivative which was then subjected to the Pinner amidine reaction protocols followed by usual methods of purification to afford the title compound as colorless crystals (145 mg, 34.8%). ¹ HNMR (CD₃ OD)δ: 8.07 (d, J=7.7 Hz, 1H), 7.96 (d, J=7.3 Hz, 1H), 7.82 (s, 1H), 7.78 (d, J=7.7 Hz, 1H), 7.73 (d, J=8.1 Hz, 1H), 7.61 (d, J=8.5 Hz, 2H), 7.57 (d, J=8.8 Hz, 1H), 7.49 (t, J=7.7 Hz, 1H), 7.37 (d, J=8.4 Hz, 2H), 7.29 (d, J=7.7 Hz, 1H), 2.32 (s, 3H); ¹³ C NMR (CD₃ OD)δ: 167.63, 157.41, 143.05, 141.47, 139.26, 138.46, 138.32, 137.59, 135.51, 134.27, 133.63, 132.91, 131.48, 131.22, 130.84, 129.98, 128.74, 128.61, 128.43, 120.98, 12.22; ESMS: m/z 509.1 (M+H, 100); HRMS: calcd. for C₂₄ H₂₂ Cl₁ N₆ O₃ S₁ 509.1163 found 509.1172.

EXAMPLE 132 5-(3-amidinophenyl)-2-methyl-4-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]imidazole

Part A: Ethyl-2-methyl-4-(3'cyano)phenyl-5-carboxylate was prepared via the reaction of ethyl-2-bromo-(3-cyano)benzoylacetate and ammonium acetate in acetic acid in 20% yield. ¹ HNMR (CDCl₃) δ: 10.03 (BS, 1H), 8.25 (bs, 1H), 8.17 (bd, 1H), 7.40 (d, 1H), 7.44 (t, 1H), 4.30 (q, 2H), 2.50 (s, 3H), 1.30 (t, 3H) ppm; Ammonia CI mass spectrum 272 (M+H, 100).

Part B: Weinreb coupling of the product from part A with the -2'tert-butylaminosulfonyl-1-aminobiphenyl and trimethyl aluminum afforded the desired coupled product which when subjected to the standard Pinner amidine reaction and the usual purification protocols to afford the title compound as colorless crystals; ¹ HNMR (CD₃ OD)δ: 8.29 (s, 1H), 8.10 (dd, J=7.9 Hz, J=1.2 Hz, 1H), 8.06 (d, J=7.8 Hz, 1H), 7.83 (d, J=7.6 Hz, 1H), 7.73 (d, J=7.8 Hz, 1H), 7.70 (bs, 2H), 7.61 (td, J=7.6 Hz, J=1.5 Hz, 1H), 7.52 (td, J=7.6 Hz, J=1.5 Hz, 1H), 7.42 (d, J=6.8 Hz, 2H), 7.33 (dd, J=7.6 Hz, J=1.2 Hz, 1H), 2.53 (bs, 3H); ESMS: m/z 475.1 (M+H, 100) for C₂₄ H₂₂ N₆ O₃ S₁.

EXAMPLES 133 AND 134 1-(3-amidinophenyl)-3-methyl-5-[(4'-(benzimidazol-1-yl)phen-1-yl)aminocarbonyl]pyrazole and 1-(3-aminocarbonylphenyl)-3-methyl-5-[(4'-(benzimidazol-1-yl)phen-1-yl)aminocarbonyl]pyrazole

Part A. Preparation of N-(4-nitrophenyl)benzimidazole

Made a suspension of 1.26 g of 4-bromonitrobenzene and 0.74 g of benzimidazole in 50 mL of anhydrous dimethylformamide. Added 0.94 g of potassium carbonate to reaction mixture. Warmed reaction mixture to 80° C. for 72H. Diluted reaction mixture with 100 mL water and extracted 3 times with 50 mL ethyl acetate portions. Combined extracts and dried. Filtered and concentrated resulting organics in vacuo to give the crude product. LRMS (NH3-CI): 240, (M+H, 100), ¹ HNMR (CDCl₃)δ: 8.50 (d, 2H), 8.20 (s, 1H), 7.93 (complex, 1H), 7.75 (d, 2H), 7.63 (complex, 1H), 7.42 (complex, 2H).

Part B. Preparation of N-(4-aminophenyl)benzimidazole

Made a suspension of 0.6 g crude N-(4-nitrophenyl)benzimidazole and a catalytic amount of 10% palladium on carbon in 20 mL methanol. Placed reaction mixture under 1 atmosphere of hydrogen and let stir for 15H. Passed reaction mixture through a 1" celite pad and concentrated filtrate in vacuo to give the crude product. LRMS (NH3-CI): 210 (M+H, 100), ¹ HNMR (DMSO-d6)δ: 9.25 (s, 1H), 7.83 (complex, 1H), 7.60 (complex, 1H), 7.47 (complex, 2H), 7.35 (d, 2H), 6.80 (d, 2H).

Part C. Preparation of N-(3-cyanophenyl)-3-methyl-5-[(4'-(benzimidazol-1-yl)phen-1-yl)aminocarbonyl]pyrazole

To 0.16 g of N-(3-cyanophenyl)-3-methyl-pyrazole 5-carboxylic acid and 25 mL dichloromethane was added 0.07 mL oxalyl chloride and 2 drops DNF. The reaction proceded overnight. Concentration of the reaction mixture-and placement under high vacuum gave the crude acid chloride which was then coupled to the product of part B under standard conditions to afford crude N-(3-cyanophenyl-)3-methyl-5-((4'-N-benzimidazol-1-yl-phenyl)aminocarbonyl)pyrazole. LRMS (ESI):419 (M+H, 20), 210 (M+2H)⁺⁺.

Part D. Preparation of N-(3-amidinophenyl)-3-methyl-5-[(4'-benzimidazol-1-yl)phen-1-yl)aminocarbonyl]pyrazole

Standard transformation of the benzonitrile obtained in part C to the benzamidine via the ethyl imidate converted 0.24 g of the crude benzonitrile to 0.02 g of the benzamidine bis-TFA salt after standard HPLC purification. LRMS (ES+): 436.21 (M+H), HRMS (FAB): Calc: 436.188584 Mass: 436.191317 and 0.003 g of the benzamide LRMS (ES+): 437 (M+H), 459 (M+Na), HRMS (NH3-CI): Calc:437.172599 Mass:437.173670. ¹ HNMR (DMSO-d6, 300 MHz)δ: 10.76 (s, 1H), 9.40 (s, 2H), 9.02 (s, 2H), 8.59 (s, 1H), 7.94 (s, 1H), 7.88 (d, 2H), 7.76 (complex, 3H), 7.64 (complex, 4H), 7.32 (complex, 2H), 7.05 (s, 1H), 2.30 (s, 3H).

EXAMPLES 135 AND 136 1-(3-amidinophenyl)-3-methyl-5-[(4'-(2-methylimidazolyl)phenyl) aminocarbonyl pyrazole and 1-(3-aminocarbonyl]phenyl)-3-methyl-5-[(4'-(2-methylimidazolyl)phenyl)aminocarbonyl)pyrazole

Part A. Preparation of N-(4-nitrophenyl)-2-methylimidazole

2-Methylimidazole (1.04 g) was treated with 0.56 g 60% sodium hydride in an oil dispersion in 60 mL DMF with cooling. After 0.33H added 4-bromonitrobenzene in three portions over 0.5 H. Let reaction mixture warm to ambient temperature overnight. Diluted mixture with 100 mL of 1.0M HCl solution and extracted three times with 30 mL portions of ethyl acetate. Combined extracts and dried over magnesium sulfate. Concentrated resulting organics in vacuo. Purified crude material by standard chromatographic techniques to give the purified product as a crystalline solid. LRMS (NH3-CI): 204 (M+H, 100); ¹ HNMR (CDCl₃) δ: 8.40 (d, 2H), 7.50 (d, 2H), 7.05 (d, 2H), 2.43 (s, 3H).

Part B. Preparation of 1-(4-aminophenyl)-2-methylimidazole

N-(4-nitrophenyl)-2-methylimidazole (0.47 g) was treated with a catalytic amount of 10% palladium on carbon in 15 mL methanol. The mixture was placed under an atmosphere of hydrogen. The reaction mixture was stirred for 3H and then passed through a 1" celite pad. The resulting filtrate was concentrated under reduced pressure to give the title compound. LRMS (NH₃ -CI): 174 (M+H, 100), ¹ HNMR (CDCl₃)δ: 7.05 (d, 1H), 6.97 (d, 2h), 6.77 (d, 1H), 6.60 (d, 2H), 5.34 (s, 2H), 2.13 (s, 3H).

Part C. Preparation of N-(3-cyanophenyl)3-methyl-5-((4'-2-methylimidazolylphenyl)aminocarbonyl)pyrazole

To 0.24 g of N-(3-cyanophenyl)-3-methyl-pyrazole 5-carboxylic acid and 20 mL dichloromethane was added 0.14 mL oxalyl chloride and 2 drops DMF. The reaction proceeded overnight. Concentration of the reaction mixture and placement under high vacuum gave the crude acid chloride which was then coupled to the product of part B under standard conditions to afford the title compound isolated as the hydrochloride salt. LRMS (ESI):383 (M+H, 100), ¹ HNMR (DMSO-d₆) δ: 10.90 (s, 1H), 7.95 (s, 1H), 7.90 (d, 2H), 7.83 (m, 2H), 7.75 (m, 2H), 7.63 (m, 1H), 7.57 (d, 2H), 7.10 (s, 1H), 2.49 (s, 3H), 2.30 (s, 3H).

Part D. Preparation of 1-(3-amidinophenyl)-3-methyl-5-[(4'-2-methylimidazolyl)phenyl)aminocarbonyl]pyrazole and 1-(3-aminocarbonylphenyl)-3-methyl-5-[(4'-2-methylimidazolyl)phenyl)aminocarbonyl]pyrazole

The N-(3-cyanophenyl)-3-methyl-5-((4'-2-methylimidazolylphenyl)aminocarbonyl)pyrazole was converted to the corresponding benzamidine via Pinner synthesis and amidination by subsequent treatment of the imidate with ammonium carbonate. The crude mixture was then purified by standard HPLC technique to give the benzamidine as a white solid after lyophilization LRMS (ES+):400 (M+H, 100); HRMS: Calc:400.188584, Mass:400.188113 ¹ HNMR (DMSO-d₆, 300 MHz)δ: 10.87 (s, 1H), 9.40 (s, 2H), 9.30 (s, 2H), 7.95 (s, 1H), 7.89 (d, 2H), 7.80 (m, 2H), 7.75 (m, 2H), 7.65 (m, 1H), 7.55 (d, 2H), 7.05 (s, 1H) 2.47 (s, 3H), 2.30 (S, 3H). The corresponding benzamide was isolated as a by-product during purification. LRMS (ES+): 401 (M+H) HRMS (NH₃ -CI): Calc. 401.172599 Mass: 410.170225; ¹ HNMR (DMSO-d₆, 300 MHz)δ: 10.77 (s, 1H), 8.78 (s, 1H), 8.09 (s, 1H), 7.94 (s, 1H), 7.87 (m, 3H), 7.77 (m, 1H), 7.65 (d, 2H), 7.63 (m, 1H), 7.50 (complex, 3H), 7.36 (m, 2H), 6.95 (s, 1H), 2.30 (s, 3H).

EXAMPLE 137 1-(3-amidinophenyl)-3-methyl-5-[[4'-(1,2,4-triazol-2-yl)-phenyl]aminocarbonyl]pyrazole

Part A. 1-(3-cyanophenyl)-3-methyl-5-((4'-(1,2,4-triazolyl)phenyl)aminocarbonyl)pyrazole

The pyrazole acid chloride was generate by standard method and coupled to 0.18 g of commercially available 4-(1-N-1,2,4-triazolo)aniline using the standard DMAP coupling to give the 1-(3-cyanophenyl)-3-methyl-5-((4'-(1,2,4-triazol-1-yl)phenyl)aminocarbonyl)pyrazole. The crude product was recrystallized from 2:1 methylene chloride to methanol to give the product as a white solid. LRMS (NH₃ -CI) :370 (M+H), ¹ HNMR (DMSO-d₆, 300 MHz) δ: 10.57 (s, 1H), 9.20 (s, 1H), 8.19 (s, 1H), 7.97 (s, 1H), 7.80 (complex, 6H), 7.65 (t, 1H), 7.00 (s, 1H), 2.29 (s, 3H).

Part B. Preparation of 1-(3-amidinophenyl)-3-methyl-5-((4'-(1,2,4-triazolyl)phenyl)aminocarbonyl)pyrazole

Standard transformation of the benzonitrile obtained in part A to the benzamidine via the ethyl imidate converted 0.13 g of the benzonitrile to the benzamidine bis-TFA salt after standard HPLC purification. LRMS (ES+): 387 (M+H) HRMS (NH3-CI): Calc: 387.168182 Mass: 387.166790; ¹ HNMR (DMSO-d₆, 300 Mhz)δ: 10.70 (s, 1H), 9.39 (s, 2H), 9.20 (2, 1H), 9.02 (s, 2H), 8.19 (s, 1H), 7.91 (s, 1H), 7.79 (m, 5H), 7.70 (m, 2H), 7.02 (s, 1H), 2.31 (s, 3H).

EXAMPLE 138 1-(3-amidinophenyl)-3-methyl-5-((4'-cyclohexylphenyl)aminocarbonyl)pyrazole

Part A. Preparation of 1-(3-cyanophenyl)-3-methyl-5-((4'-cyclohexylphenyl)aminocarbonyl)pyrazole

The pyrazole acid chloride was generate in the standard method and coupled to 0.19 g of commercially available 4-cyclohexylaniline using the standard DMAP coupling to give the 1-(3-cyanophenyl)-3-methyl-5-((4'-cyclohexylphenyl)aminocarbonyl)pyrazole. LRMS (NH₃ -CI):385 (M+H), 402 (M+NH₄), ¹ HNMR (DMSO, 300 MHz)δ: 10.40 (s, 1H), 7.92 (s, 1H), 7.82 (d, 1H), 7.72 (d, 1H), 7.61 (t, 1H), 7.50 (d, 2H), 7.13 (d, 2H), 6.92 (s, 1H), 3.31 (s, 1H), 2.25 (s, 3H), 1.71 (complex, 5H), 1.13 (complex, 5H).

Part B. Preparation of 1-(3-amidinophenyl)-3-methyl-5-((4'-cyclohexylphenyl)aminocarbonyl)pyrazol

Standard transformation of the benzonitrile obtained in part A to the benzamidine via the ethyl imidate converted the crude benzonitrile to the benzamidine TFA salt. The crude product was purified by standard HPLC purification. LRMS (ES+): 402 (M+H) HRMS (NH3-CI): Calc: 402.229386 Mass: 402.227504 ¹ HNMR (DMSO-d₆, 300 MHz)δ: 10.30 (s, 1H), 9.38 (s, 2H), 9.07 (s, 2H), 7.90 (s, 1H), 7.77 (m, 1H), 7.69 (m, 2H), 7.50 (d, 2H), 7.12 (d, 2H), 6.93 (s, 1H), 3.31 (m, 1H), 2.28 (s, 3H), 1.71 (complex, 5H), 1.32 (complex, 5H).

EXAMPLE 139 1-(3-amidinophenyl)-3-methyl-5-[[1,1']-biphen-4-ylaminocarbonyl]pyrazole

Part A. Preparation of 1-(3-cyanophenyl)-3-methyl-5-[[1,1']-biphen-4-ylaminocarbonyl]pyrazole

The pyrazole acid chloride was generate by standard method and coupled to 0.19 g of commercially available 4-aminobiphenyl using standard DMAP coupling to give the 1-(3-cyanophenyl)-3-methyl-5-[[1,1']-biphen-4-ylaminocarbonyl]pyrazole. LRMS (NH₃ -CI):379 (M+H), 396 (M+NH4) HRMS (NH₃ -CI): Calc:396.182436 Mass:396181736. ¹ HNMR (DMSO-d₆, 300 MHz)δ10.57 (s, 1H), 9.20 (s, 1H), 8.19 (s, 1H), 7.97 (s, 1H), 7.80 (complex, 6H), 7.65 (t, 1H), 7.00 (s, 1H), 2.29 (s, 3H).

Part B. Preparation of 1-(3-amidinophenyl)-3-methyl-5-[[1,1']-biphen-4-ylaminocarbonyl]pyrazole

Standard transformation of the benzonitrile obtained in part B to the benzamidine via the ethyl imidate converted of the crude benzonitrile to the benzamidine TFA salt. The crude product was purified by standard HPLC purification technique. LRMS (ES+): 396 (M+H) HRMS (NH3-CI): Calc: 396.181736 Mass: 396.182436; ¹ HNMR (DMSO, 300 MHz)δ: 10.60 (s, 1H), 9.40 (s, 2H), 8.99 (s, 2H), 7.91 (m, 1H), 7.80 (complex, 5H), 7.61 (m, 4H), 7.41 (m, 2H), 7.30 (m, 1H), 7.00 (s, 1H), 2.29 (s, 3H).

EXAMPLE 140 1-(3-amidinophenyl)-3-methyl-5-((4'-morpholinophenyl)aminocarbonyl)pyrazole

Part A. 1-(3-cyanophenyl)-3-methyl-5-((4'-morpholinophenyl)aminocarbonyl)pyrazole

The pyrazole acid chloride was generate from the pyrazole acid by standard method and coupled to 0.26 g of commercially available 4-morpholinoaniline using the standard DMAP coupling to give the 1-(3-cyanophenyl)-3-methyl-5-((4'-morpholinophenyl)aminocarbonyl)pyrazole. LRMS (NH3-CI):388 (M+H), ¹ HNMR (DMSO, 300 MHz)δ: 10.30 (s, 1H), 7.90 (m, 1H), 7.82 (d, 1H), 7.71 (m, 1H), 7.62 (t, 6H), 7.49 (d, 2H), 6.89 (s, 1H), 6.87 (d, 2H), 3.69 (t, 4H), 3.02 (t, 4H), 2.25 (s, 3H).

Part B. Standard transformation of the benzonitrile obtained in part A to the benzamidine via the ethyl imidate converted the crude benzonitrile to the benzamidine bis-TFA salt. The crude product was purified by standard HPLC purification. LRMS (ES+): 405 (M+H) HRMS (NH3-CI): Calc: 405.203899 Mass: 405.201545 ¹ HNMR (DMSO-d₆, 300 MHz)δ: 10.38 (s, 1H), 9.40 (s, 2H), 9.12 (s, 2H), 7.90 (s, 1H), 7.78 (d, 1H), 7.68 (m, 2H), 7.49 (d, 2H), 6.92 (s, 1H), 6.90 (d, 2H), 3.80 (t, 4H), 3.01 (t, 4H), 2.29 (s, 3H).

EXAMPLE 141 1-(3-amidinophenyl)-3-methyl-5-[(4'-((2-trifluoromethyl)tetrazol-1-yl)phenyl)aminocarbonyl]pyrazole

Part A. Preparation 4-(2-trifluoromethyltetrazolyl)nitrobenzene

3.0 g of commercially available 4-nitroaniline was trifluoromethylacetylated in the presence of trifluoroacetic anhydride to give the crude N-trifluoroacetyl-4-nitroaniline. LRMS (NH₃ -CI): 252 (M+NH4); ¹ HNMR (DMSO-d6, 300 Mhz)δ: 11.75 (s, 1H), 8.28 (d, 2H), 7.92 (d, 2H) The crude material was then treated with triphenylphosphine in carbon tetrachloride to give the chloroimine. ¹ HNMR (CDCl₃, 300 MHz)δ: 8.35 (d, 2H), 7.15 (d, 2H). The crude chloroimine was cyclized to the 4-(2-trifluoromethyltetrazole)nitrobenzene with sodium azide in acetonitrile. ¹ HNMR (CDCl₃, 300 MHz)δ: 8.54 (d, 2H), 7.80 (d, 2H). The crude 2-trifluoromethyltetrazoloaniline was triturated to give the semi-crude product which was catalytically reduced to the aniline with 10% palladium on carbon. LRMS (NH₄ -CI): 230 (M+H), 247 (M+NH4), ¹ HNMR (DMSO-d₆, 300 MHz)δ: 7.256 (d, 2H), 6.65 (d, 2H).

Part B. Preparation of 1-(3-cyanophenyl)-3-methyl-5-[(4'-((2-trifluoromethyl)tetrazolyl)phenyl)aminocarbonyl]pyrazole

The pyrazole acid chloride was generate by standard method and coupled to 0.49 g of 4-(2-trifluoromethyltetrazole)aniline using the standard DMAP coupling to give the 1-(3-cyanophenyl)-3-methyl-5-((4'-(2-trifluoromethyltetrazol)-1-yl-phenyl)aminocarbonyl)pyrazole. LRMS (NH₃ -CI):439 (M+H), 461 (M+Na+), 877 (2 M+H), 899 (2M+Na); ¹ HNMR (DMSO-d₆, 300 MHz)δ: 10.87 (s, 1H), 8.00 (s, 1H), 7.91 (d, 2H), 7.84 (m, 1H), 7.77 (m, 1H), 7.69 (d, 2H), 7.63 (t, 1H), 7.02 (s, 1H), 2.29 (s, 3H).

Part C. Preparation of 1-(3-amidinophenyl)-3-methyl-5-[(4'-((2-trifluoromethyl)tetrazolyl)phenyl)aminocarbonyl]pyrazole

Standard transformation of the benzonitrile obtained in part B to the benzamidine via the ethyl imidate converted the crude benzonitrile to the benzamidine TFA salt after HPLC purification. LRMS (ES+): 456 (M+H) HRMS (NH₃ -CI): Calc: 456.150816 Mass: 456.150428; ¹ HNMR(DMSO-d₆, 300 MHz)δ: 10.92 (s, 1H), 9.40 (s, 2H), 9.18 (s, 2H), 7.90 (complex, 3H), 7.78 (m, 2H), 7.67 (complex, 3H), 7.08 (s, 1H), 2.32 (s, 3H).

EXAMPLE 142 1-(3-aminomethylphenyl)-3-methyl-5-[(4'-((2-trifluoromethyl)tetrazol-1-yl)phenyl)aminocarbonyl]pyrazole

0.06 g of 1-(3-cyanophenyl)-3-methyl-5-((4'-(2-trifluoromethyltetrazolyl)phenyl)aminocarbonyl)pyrazole was reacted with 10% palladium on carbon in TFA/methanol under a hydrogen atmosphere. After a few hours the reaction mixture was filtered through a 1 inch celite pad. The filtrate was concentrated under reduced pressure and the residue was purified by standard HPLC method to give the desired compound. LRMS (NH₄ -CI): 443 (M+H) HRMS (NH₄ -CI): calc: 443.155567 mass: 443.155567; ¹ HNMR (DMSO-d₆, 300 MHz)δ: 10.90 (s, 1H), 8.20 (brd. s, 2H), 7.90 (d, 2H), 7.69 (d, 2H), 7.62 (s, 1H), 7.42 (complex, 3H), 6.97 (s, 1H), 4.09 (m, 2H), 2.29 (s, 3H).

EXAMPLE 143 1-(3-amidinophenyl)-3-methyl-5-[((4'-(N,N-dimethylamino)carbonylamino)phen-1'-yl)aminocarbonyl]pyrazole

Part A. Preparation of 4-((N,N-dimethylamino)carbonylamino)-1-nitrobenzene

1.56 g of 4-nitroaniline was treated with 0.50 g sodium hydride in 60% oil dispersion in DMF at 0° C. After 20 minutes added 1.04 mL of N,N-dimethylcarbamyl chloride dropwise. Let mixture warm to ambient temperature overnight. Poured reaction mixture into 150 mL ice water. Let stand for 1h. Isolated precipitate via vacuum filtration. LRMS (NH₃ -CI): 210 (M+H), 227 (M+NH₄), ¹ HNMR (DMSO-d₆, 300 MHz)δ: 8.97 (s, 1H), 8.12 (d, 2H), 7.70 (d, 2H)2.91 (s, 6H).

Part B. Preparation of 1-amino-4-((N,N-dimethylamino)carbonylamino)benzene

Treated 1.66 g of 4-N,N-dimethylurea nitrobenzene with a catalytic amount of 10% palladium on carbon in methanol and placed under 35 psi hydrogen for 1H. Passed through a 1 inch celite pad and concentrated filtrate to give a solid after high vacuum. LRMS (NH3-CI): 180 (M+H).

Part C. Preparation of 1-(3-cyanophenyl)-3-methyl-5-[(4'-((N,N-dimethylamino)carbonylamino)phen-1'-yl)aminocarbonyl]pyrazole

0.37 g of 4-N,N-dimethylurea aniline was coupled to 0.46 g of N-(3-cyanophenyl)-3-methyl-pyrazole-5-carboxylic acid chloride via standard DMAP coupling in dichloromethane. A few drops of DMF was added to catalyze the reaction. The N-(3-cyanophenyl)-3-methyl-pyrazole-5-carboxylic acid chloride was prepared by the previously disclosed procedure. The desired product was purified by standard purification techniques. LRMS (ES+): 389 (M+H), 411 (M+Na+), 777 (2M+H), 799 (2M+Na), ¹ HNR(DMSO-d₆, 300 MHz)δ: 10.35 (s, 1H), 8.22 (s, 1H), 7.91 (s, 1H), 7.82 (d, 1H), 7.71 (d, 1H), 7.63 (t, 1H), 7.46 (d, 2H), 7.37 (d, 2H), 6.91 (s, 1H), 2.88 (s, 6H), 2.29 (s, 3H).

Part D. Preparation of 1-(3-amidinophenyl)-3-methyl-5-[(4'-((N,N-dimethylamino)carbonylamino)phen-1'-yl)aminocarbonyl]pyrazole

Standard transformation of the benzonitrile obtained in part C to the benzamidine via the ethyl imidate converted the crude benzonitrile to the benzamidine TFA salt after HPLC purification. LRMS (ES+): 406 (M+H), 811 (H+-dimer) HRMS (NH₃ -CI): Calc: 406.199148 Mass: 406.198887; ¹ HNMR (DMSO-d₆, 300 MHz)δ: 10.37 (s, 1H), 9.40 (s, 2H), 9.02 (s, 2H), 8.23 (s, 1H), 7.91 (s, 1H), 7.78 (d, 1H), 7.68 (m, 2H), 7.43 (d, 2H), 7.38 (d, 2H), 6.95 (s, 1H), 2.87 (s, 6H), 2.29 (s, 3H).

EXAMPLES 144 AND 145 1-(3-amidinophenyl)-3-methyl-5-[(4'-(N,N-diethylamino)phenyl)arainocarbonyl]pyrazole (Example 144) and 1-(3-aminocarbonylphenyl)-3-methyl-5-((4'-N,N-diethylamino)phenyl)aminocarbonyl)pyrazole (Example 145)

Part A. Preparation of 1-(3-cyanophenyl)-3-methyl-5-[(4'-(N,N-diethylamino)phenyl)aminocarbonyl]pyrazole

The pyrazole acid chloride was generated by the standard method and coupled to 0.24 g of commercially available N,N-diethyl-1,4-phenylenediamine using the standard DMAP coupling to give the 1-(3-cyanophenyl)-3-methyl-5-((4'-N,N-diethylaminoaniline)aminocarbonyl)pyrazole. LRMS (NH₃ -CI):374 (M+H), 747 (2M+H); ¹ HNMR (DMSO-d₆, 300 MHz)δ: 10.16 (s, 1H), 7.90 (s, 1H), 7.81 (m, 1H), 7.71 (m, 1H), 7.60 (t, 1H), 7.37 (d, 2H), 6.88 (s, 1H), 6.59 (d, 2H), 3.26 (m, 4H), 2.25 (s, 3H), 1.02 (t, 6H).

Part B. Preparation of 1-(3-amidinophenyl)-3-methyl-5-[(4'-(N,N-diethylamino)phenyl)aminocarbonyl]pyrazole

Standard transformation of the benzonitrile obtained in part B to the benzamidine via the ethyl imidate converted 0.24 g of the crude benzonitrile to 0.256 g of the benzamidine bis-TFA salt after HPLC purification. LRMS (ES+): 391 (M+H) HRMS (NH₃ -CI): Calc: 391.224635 Mass: 391.224109. 0.017 g of the benzamide was also isolated during HPLC purification. LRMS (ESI+): 392 (M+H) HRMS (NH₃ -CI): calc: 392.208650 mass: 392.207700.

EXAMPLES 146 AND 147 1-(3-amidinophenyl)-3-methyl-5-[(4'-(1-tetrazolyl)phenyl)aminocarbonyl)pyrazole (Example 146) and 1-(3-aminocarbonylphenyl)-3-methyl-5-((4'-(1-tetrazolyl)phenyl)aminocarbonyl)pyrazole (Example 147)

Part A. Preparation of 4-N-formylaminonitrobenzene

Treated 0.69 g of 4-aminonitrobenzene with acetic formic anhydride in THF at 0° C. Then warmed reaction mixture to 55° C. for 2H. Concentrated mixture under reduced pressure and placed residue on high vacuum to give the crude product. LRMS (NH₃ -CI): 184 (M+NH4).

Part B. Preparation of 4-(1-tetrazolyl)nitrobenzene

Made a solution of above compound, 2.63 g triphenylphosphine, 1.15 g TMS azide and 1.75 g DEAD reagent in THF. Let stir for 24H. Diluted reaction mixture with water and extracted with methylene chloride. Dried and concentrated organic extracts to give the crude product which was purified by standard chromatographic technique. LRMS (NH₃ -CI): 209 (M+NH4), ¹ HNMR (DMSO-d₆, 300 MHz)δ: 10.35 (s, 1H), 8.48 (d, 2H), 8.20 (d, 2H).

Part C. Preparation of 4-(1-tetrazolyl)aniline

Treated 4-(1-tetrazolyl)nitrobenzene with 10% palladium on carbon in methanol and placed under 40 psi of hydrogen for 2H. Passed reaction mixture through a 1 inch celite pad and concentrated filtrate to give the crude product. LRMS (NH₃ -CI): 162 (M+H), 179 (M+NH4), ¹ HNMR (DMSO-d₆, 300 MHz)δ: 9.79 (s, 1H), 7.42 (d, 2H), 6.67 (d, 2H).

Part D. Preparation of 1-(3-cyanophenyl)-3-methyl-5-[(4'-(1-tetrazolyl)phenyl)aminocarbonyl]pyrazole

The pyrazole acid chloride was generate in the standard method and coupled to 0.26 g 4-(1-tetrazolyl)aniline using the standard DMAP coupling to give the 1-(3-cyanophenyl)-3-methyl-5-((4'-(1-tetrazolyl)phenyl)aminocarbonyl)pyrazole. This crude material was used directly.

Part E. Preparation of 1-(3-amidinophenyl)-3-methyl-5-((4'-(1-tetrazolyl)phenyl)aminocarbonyl)pyrazole

Standard transformation of the benzonitrile obtained in part D to the benzamidine via the ethyl imidate converted the crude benzonitrile to 0.014 g of the benzamidine TFA salt after HPLC purification. LRMS (ES+): 388 (M+H) HRMS (NH₃ -CI): Calc: 388.163431 Mass: 388.165343 ¹ HNMR (DMSO-d₆, 300 MHz)δ: 10.79 (s, 1H), 10.01 (s, 1H), 9.40 (bs, 2H), 8.99 (bs, 2H), 7.93 (s, 1H), 7.85 (m, 4H), 7.77 (m, 2H), 7.67 (m, 1H), 7.04 (s, 1H), 2.31 (s, 3H). 0.007 g of the benzamide was also isolated during HPLC purification. LRMS (ESI+): 799 (2M+Na) 777 (2M+H) HRMS (NH₃ -CI): calc: 389.147447 mass:389.149952; ¹ HNMR (DMSO-d₆, 300 MHz)δ: 10.77 (s, 1H), 10.00 (s, 1H), 7.94 (m, 1H), 7.87 (m, 6H), 7.51 (m, 1H), 6.96 (s, 1H), 2.30 (s, 3H).

EXAMPLES 148, 149, AND 150 1-(3-amidinophenyl)-3-methyl-5-[(4'-(N-acetylpiperizin-1-yl)phenyl)aminocarbonyl]pyrazole, 1-(3-amidinophenyl)-3-methyl-5-[(4'-(N-tert-butyloxycarbonylpiperizin-1-yl)phenyl)aminocarbonyl]pyrazole, and 1-(3-amidinophenyl)-3-methyl-5-((4'-piperizin-1-yl-phenyl)aminocarbonyl)pyrazole

Part A. Preparation of 1-(3-cyanophenyl)-3-methyl-5-[(4'-(N-tert-butyloxycarbonylpiperizin-1-yl)phenyl)aminocarbonyl]pyrazole

The pyrazole acid chloride was generate by the standard method and coupled to 0.23 g of 4-(N-boc-piperizine)aniline (which is readily available from commercially available 1-(4-nitrophenyl)piperazine) using the standard DMAP coupling to give the crude 1-(3-cyanophenyl)-3-methyl-5-((4'-N-tert-butyloxycarbonylpiperizine-1-phenyl)aminocarbonyl)pyrazole. The crude product was purified by standard chromatographic technique. LRMS (NH₃ -CI):487 (M+H) ¹ HNMR (DMSO-d₆, 300 Mz)δ: 10.60 (s, 1H), 7.90 (s, 1H), 7.81 (m, 1H), 7.73 (m, 1H), 7.61 (t, 1H), 7.47 (d, 2H), 6.90 (s, 1H), 6.88 (d, 2H), 3.41 (complex, 4H), 3.01 (complex, 4H), 2.28 (s, 3H), 1.37 (s, 9H).

Part B. Preparation of 1-(3-amidoximephenyl)-3-methyl-5-[(4'-(N-tert-butyloxycarbonylpiperizin-1-yl)phenyl]aminocarbonyl]pyrazole

Treated 0.29 g of 1-(3-cyanophenyl)-3-methyl-5-((4'-N-tert-butyloxycarbonylpiperizin-1-ylphenyl)aminocarbonyl)pyrazole with 0.15 g hydroxylamine hydrochloride and 0.11 g of sodium carbonate in ethanol/water. Warmed reaction mixture to reflux temperature for 5H. Worked up reaction mixture with aqueous washings, dried resulting organic, and concentrated in vacuo to give the crude amidoxime.

Part C. Preparation of 1-(3-amidinophenyl)-3-methyl-5-[(4'-(N-tert-butyloxycarbonylpiperizin-1-yl)phenyl)aminocarbonyl]pyrazole and 1-(3-amidinophenyl)-3-methyl-5-[(4'-(N-acetylpiperazin-1-yl)phenyl)aminocarbonyl]pyrazole

Treated crude amidoxime with acetic acid and acetic anhydride for 0.5H. Added a catalytic amount of 10% palladium on carbon to reaction mixture and placed on Parr hydrogenator at 50 psi for 4H. Passed through a 1 inche celite pad and concentrated filtrate to give the crude benzamidine. Purified via standard HPLC technique. The N-acetyl compound LRMS (ES+): 446 (M+H, 100) HRMS (FAB+): calc. -446.230448 mass-446.231327 ¹ HNMR (DMSO-d₆, 300 MHz)δ: 10.33 (s, 1H), 9.39 (bs, 2H), 9.04 (bs, 2H), 7.90 (s, 1H), 6.77 (d, 1H), 7.68 (m, 2H), 7.48 (d, 2H), 6.94 (s, 1H), 6.90 (d, 2H), 3.52 (m, 4H), 3.02 (M, 4H), 2.28 (s, 3H), 2.00 (s, 3H). 1-(3-amidinophenyl)-3-methyl-5-[(4'-(N-acetylpiperazin-1-yl)phenyl)aminocarbonyl]pyrazole was isolated as a by-product in addition to the N-boc compound LRMS (ES+): 504 (M+H) HRMS (NH₃ -CI): calc-504.272313 mass-504.272536 ¹ HNMR (DMSO-d₆, 300 MHz)δ: 10.34 (s, 1H), 9.38 (bs, 2H), 9.05 (bs, 2H), 7.90 (m, 1H), 7.77 (m, 1H), 7.67 (m, 2H), 7.47 (d, 2H), 6.94 (s, 1H), 6.90 (d, 2H), 3.42 (m, 4H), 3.00 (m, 4H), 2.29 (s, 3H), 1.37 (s, 9H).

Part D. Preparation of 1-(3-amidinophenyl)-3-methyl-5-[(4'-(N-piperizin-1-yl)phenyl)aminocarbonyl]pyrazole

0.043 g of 1-(3-amidinophenyl)-3-methyl-5-((4'-N-tert-butyloxycarbonylpiperizin-1-phenyl)aminocarbonyl)pyrazole was treated with TFA at ambient temperature for 3H. Concentrated reaction mixture under reduced pressure to give the crude product. Purified crude material by standard HPLC technique. LRMS (ES+): 404 (M+H) HRMS (NH₃ -CI): calc-404.219884 mass-404.221193 ¹ HNMR (DMSO-d₆, 300 MHz)δ: 10.36 (s, 1H), 9.39 (bs, 2H), 9.18 (bs, 2H), 7.90 (s, 1H), 7.77 (d, 1H), 7.67 (m, 2H), 7.01 (d, 2H), 6.92 (m, 3H), 3.22 (m, 8H), 2.29 (s, 3H).

EXAMPLE 151 1-(3-amidinophenyl)-3-trifluoromethyl-5-((4'-cyclohexylphenyl)aminocarbonyl)pyrazole

Part A. Preparation of 1-(3-cyanophenyl)-3-trifluoromethyl-5-((4'-cyclohexylphenyl)aminocarbonyl)pyrazole

0.25 g of N-(3-cyanophenyl)-3-methyl-pyrazole-5-carboxylic acid was converted to its corresponding acid chloride by standard procedure and reacted with 0.15 g of 4-cyclohexylaniline in the presence of DMAP in methylene chloride to afford the title compound after workup and purification by standard chromatographic technique. LRMS (ES+): 461 (M+Na+), 899 (Na+-dimer), ¹ HNMR (DMSO-d₆, 300 MHz)δ: 10.57 (s, 1H), 8.13 (s, 1H), 7.95 (d, 1H), 7.86 (d, 1H), 7.69 (t, 1H), 7.65 (s, 1H), 7.50 (d, 2H), 7.15 (d, 2H), 2.41 (complex, 1H), 1.70 (complex, 5H), 1.25 (complex, 5H).

Part B. Preparation of 1-(3-amidinophenyl)-3-trifluoromethyl-5-((4'-cyclohexylphenyl)aminocarbonyl)pyrazole

The cyano derivative was converted to the amidino derivative via the amidoxime as previously described. The amidoxime was reduced to the benzamidine by conversion to the corresponding acetate by acetic acid/acetic anhydride and catalytic reduction with 10% palladium on carbon under a hydrogen atmosphere, also previously described. The crude product was purified by standard HPLC technique to give the TFA salt. LRMS (ES+): 456 (M+H) HRMS (NH₃ -CI): calc-456.199783 mass-456.201120 ¹ HNMR (DMSO-d₆, 300 MHz)δ: 10.62 (s, 1H), 9.40 (s, 2H), 9.16 (s, 2H), 7.99 (s, 1H), 7.88 (m, 2H), 7.72 (t, 1H), 7.69 (s, 1H), 7.50 (d, 2H), 7.14 (d, 2H), 2.41 (complex, 1H), 1.69 (complex, 5H), 1.25 (complex, 5H).

EXAMPLE 152 1-(3-amidinophenyl)-3-methyl-5-[(4'-(N-morpholino)-3'-chlorophenyl)aminocarbonyl]pyrazole

Part A. Preparation of 1-(3-cyanophenyl)-3-methyl-5-[(4'-(N-morpholino)-3'-chlorophenyl))aminocarbonyl]pyrazole

N-(3-cyanophenyl)-3-methyl-pyrazole-5-carboxylic acid was converted to its corresponding acid chloride by standard procedure. 0.30 g of the acid chloride was reacted with 0.26 g of commercially available 2-chloro-4-morpholinoaniline in the presence of DMAP in methylene chloride to afford the product after workup and purification by standard chromatographic technique. LRMS (ES+): 422 (M+H), ¹ HNMR (DMSO-d₆, 300 MHz)δ: 10.57 (s, 1H), 8.13 (s, 1H), 7.95 (d, 1H), 7.86 (d, 1H), 7.69 (t, 1H), 7.65 (s, 1H), 7.50 (d, 2H), 7.15 (d, 2H), 2.41 (complex, 1H), 1.70 (complex, 5H), 1.25 (complex, 5H).

Part B. Preparation of 1-(3-amidinophenyl)-3-methyl-5-[(4'-(N-morpholino)-3'-chlorophenyl))aminocarbonyl]pyrazole

The cyano derivative was converted amidino derivative via the amidoxime as previously described. The amidoxime was reduced to the benzamidine by conversion to the corresponding acetate by acetic acid/acetic anhydride and catalytic reduction of the acetate with 10% palladium on carbon under a hydrogen atmosphere, also previously described. The crude product was purified by standard HPLC technique to give the bis TFA salt. LRMS (ES+): 439 (M+H) HRMS (NH₃ -CI): calc 439.164927 found 439.163814 ¹ HNMR (DMSO-d₆, 300 MHz)δ: 10.54 (s, 1H), 9.38 (s, 2H), 9.06 (s, 2H), 7.89 (s, 1H), 7.78 (m, 2H), 7.67 (m, 2H), 7.51 (dd, 1H), 7.12 (d, 1H), 6.96 (s, 1H), 3.69 (t, 4H), 2.88 (t, 4H), 2.46 (m, 3H).

EXAMPLE 153 1-(3-amidinophenyl)-5-(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl -3-(methylthio)pyrazole, Trifluoroacetic Acid Salt

Part A. Preparation of Ethyl N-(3-cyanophenyl)glycine

To a solution of 15.11 g (128 mmol) of 3-aminobenzonitrile in 200 mL of DMF under N₂ was added 23.50 g (141 mmol) of ethyl bromoacetate and 14.95 g (141 mmol) anhydrous sodium carbonate. The mixture was heated to 70° C. for 5 hours and then cooled to room temperature. Water (500 mL) was added and the mixture stirred vigorously until a precipitate formed. The solid was collected, washed with 100 mL water and then dried in vacuo to give 19.97 g (76%) of the desired compound as a yellow-orange solid. ¹ HNMR (CDCl₃)δ: 7.26 (t, 1H); 7.03 (d, 1H); 6.81 (d, 1H); 6.79 (s, 1H); 4.53 (br s, 1H); 4.03 (q, 2H); 3.92 (d, 2H); 1.21 (t, 3H).

Part B. Preparation of N-(3-cyanophenyl)glycine

To a solution of 17.00 g (83.2 mmol) of ethyl N-(3cyanophenyl)glycine in 100 mL of THF under N₂ was added 3.67 g (87.4 mmol) of lithium hydroxide monohydrate in 20 mL water. After 15 hours, the mixture was acidified with concentrated hydrochloric acid to pH 3 and a precipitate formed. The solid was collected, washed with 100 mL water and then dried in vacuo to give 14.15 g (97%) of the desired compound as a light yellow solid. ¹ HNMR (CDCl₃) δ: 7.28 (dt, 1H); 7.05 (dd, 1H); 6.83 (dd, 1H); 6.82 (d, 1H); 4.00 (s, 2H).

Part C. Preparation of N-(3-cyanophenyl)-N-nitrosoglycine

Sodium nitrite (5.54 g, 80.3 mmol) in 15 mL of water was added to a suspension of N-(3-cyanophenyl)glycine (14.15 g, 80.3 mmol) in 65 mL of water under N₂. This was allowed to stir at room temperature for 14 hours. The solution was acidified with concentrated hydrochloric acid to pH 3 and a precipitate formed. The solid was collected, washed with 50 mL water and then dried in vacuo to give 16.06 g (98%) of the desired compound as a grey solid. ¹ HNMR (CDCl₃)δ: 13.22 (br s, 1H); 8.10 (dd, 1H); 7.99 (ddd, 1H); 7.87 (dd, 1H), 7.72 (t, 1H), 4.78 (s, 2H).

Part D. Preparation of 1-(3-cyanophenyl)-4-oxy-1,2,3-oxadiazole

N-(3-cyanophenyl)-N-nitrosoglycine (6.97 g, 34 mmol) was dissolved in 32 mL of acetic anhydride and heated to 70° C. for 5 hours. The reaction mixture was cooled and then poured into 200 mL of ice-water. After stirring for 30 minutes to decompose the excess acetic anhydride, the reaction mixture was filter to provide 5.99 g (94%) of a white solid. ¹ HNNR (CDCl₃) δ: 8.08 (s, 1H), 8.02 (d, J=8.4, 1H), 7.99 (d, J=7.7, 1H), 7.82 (dd, J=8.4 , 7.7, 1H), 6.81 (s, 1H).

Part E. Preparation of 1-(3-cyanophenyl)-4-oxy-5-methylthio-1,2,3-oxadiazole

1-(3-cyanophenyl)-4-oxy-1,2,3-oxadiazole (1.48 g, 7.9 mmol) was dissolved in 30 mL of dry DMSO and cooled to 0° C. Acetyl chloride (1.25 g, 15.9 mmol) was added very slowly via syringe below the surface of the liquid under N₂. The reaction mixture was allowed to stir at room temperature for 14 hours. The reaction mixture was diluted with 100 mL Et₂ O and washed twice with 25 mL saturated aqueous NaHCO₃ Then washed three times with 25 mL water to remove the DMSO. The organic extract was dried with MgSO₄ and concentrated in vacuo to give 1.5 g of a red solid which was used without further purification. MS (NH₃ -CI) m/z 234.0 (M+H).

Part F. Preparation of methyl 1-(3-cyanophenyl)-3-methylthio-pyrazole-5-carboxylate

The crude 1-(3-cyanophenyl)-4-oxy-5-methylthio-1,2,3-oxadiazole (0.95 g, 3.90 mmol) and methyl propriolate (3.28 g, 39.1 mmol) were dissolved in 40 mL of CH₂ Cl₂ and the quartz reaction vessel was purged with N₂. The reaction mixture was irradiated in a Rayonet RPR-100 photochemical reactor for 14 hours. The crude product was concentrated in vacuo and then chromatographed with 20% EtOAc/hexanes on silica to provide 0.34 g (32%) of a yellow solid. ¹ HNMR (CDCl₃)δ: 7.77 (t, J=1.8, 1H); 7.70 (m, 2H); 7.57 (t, J=8.1, 1H); 6.94 (s, 1H); 3.83 (s, 3H); 2.57 (s, 3H).

Part G. Preparation of 1-(3-cyanophenyl)-5-[(2'-t-butylaminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-(thiomethyl)pyrazole

4-Amino-2'-methylsulfonyl-[1,1']biphenyl (65.7 mg, 0.216 mmol) was suspended in 2 mL of CH₂ Cl₂ and 0.51 mL of a 2M solution of trimethylaluminum in heptane was added slowly via syringe. The reaction was stirred for 30 minutes at room temperature and methyl 1-(3-cyanophenyl)-3-methylthio-pyrazole-5-carboxylate (56.2 mg, 0.206 mmol) was added. The reaction mixture was stirred at room temperature for an additional 14 hours. The aluminum reagent was quenched by careful addition of 1N HCl to pH 2. Then the reaction mixture extracted with 10 mL of CH₂ Cl₂ three times. The combined organic extracts were washed with water and brine, dried over MgSO₄ and the solvent evaporated. The desired product was obtained (83 mg, 74%) after silica gel chromatography with 30% EtOAc/hexane. ¹ HNMR (CDCl₃)δ: 8.16 (dd, J=7.7, 1.5, 1H); 7.84 (br s, 1H); 7.84 (t, J=1.8, 1H); 7.76 (m, 1H); 7.70-7.46 (m, 8H); 7.50 (d, J=8.8, 2H); 7.25 (d, J=7.5, 1H); 6.81 (s, 1H); 2.62 (s, 3H).

Part H. Preparation of 1-(3-amidinophenyl)-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-(methylthio)pyrazole, Trifluoroacetic Acid Salt

1-(3-Cyanophenyl)-5-[(2'-t-butylaminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-(thiomethyl)pyrazole (83 mg, 0.15 mmol) was dissolved in 5 mL of methanol and 10 mL of chloroform. The reaction mixture was cooled in an ice bath and HCl gas was bubbled in for 30 minutes to saturate the solution. The mixture was sealed and allowed to stir at room temperature for 14 hours. The solvents were removed in vacuo and the resulting solid was used in the next step.

The imidate formed above was added to 0.15 g (1.6 mmol) of ammonium carbonate and 10 mL of methanol. The mixture was allowed to stir under N₂ for 14 hours. The solvent was removed at reduced pressure. The crude benzamidine was purified by HPLC (C18 reversed phase) eluting with 0.5% TFA in H₂ O/CH₃ CN to give 64 mg (84%) of the desired salt. ¹ HNMR (DMSO-d₆)δ: 10.66 (s, 1H); 9.41 (br s, 2H); 8.97 (br s, 2H); 7.96 (m, 2H); 7.79-7.66 (m, 7H); 7.63 (d, J=9.0, 2H); 7.56 (t, J=6.6, 1H); 7.33 (d, J=9.0, 2H); 7.27 (m, 1H); 7.19 (s, 1H); 2.55 (s, 3H). HRMS 507.1268 (M+H).

EXAMPLES 154 AND 155 1-(3-amidinophenyl)-5-[(2'-aminosulfonyl-[1,1'-biphen-4-yl)aminocarbonyl]-3-(methylsulfinyl)pyrazole, Trifluoroacetic Acid Salt (Example 154) and 1-(3-amidinophenyl)-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl) aminocarbonyl]-3-(methylsulfonyl)pyrazole, Trifluoroacetic Acid Salt (Example 155)

To a solution of 1-(3-amidinophenyl)-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-(methylthio)pyrazole, trifluoroacetic acid salt (54 mg, 0.11 mmol) in 10 mL methanol was added Oxone® (66 mg, 0.11 mol) and the reaction stirred for 14 hours. The solvent was removed at reduced pressure. The crude sulfoxide was purified by HPLC (C18 reversed phase) eluting with 0.5% TFA in H₂ O/CH₃ CN to give 22 mg (38%) of the desired salt. HNMR (DMSO-d₆)δ: 10.84 (s, 1H); 9.43 (br s, 2H); 9.00 (br s, 2H); 8.00 (s, 1H); 7.99 (m, 1H); 7.87 (m, 2H); 7.75 (m, 2H), 7.65 (d, J=9.6, 2H); 7.56 (m, 2H); 7.34 (d, J=8.4, 2H); 7.27 (m, 3H); 2.99 (s, 3H). HRMS 523.1220 (M+H). Another product, the sulfone, (28 mg, 47%), was isolated from the column. HNR(DMSO-d₆)δ: 10.89 (s, 1H) 9.52 (br s, 2H); 9.09 (br s, 2H); 8.09 (s, 1H); 8.06 (d, J=7.3, 1H); 7.98 (m, 2H); 7.86 (s, 1H), 7.84 (t, J=9.0, 1H), 7.72 (d, J=8.8, 2H); 7.64 (m, 2H); 7.41 (d, J=8.4, 2H); 7.33 (m, 3H); 3.45 (s, 3H). HRMS 539.1175 (M+H).

EXAMPLE 156 1-(3-aminocarbonylphenyl)-5-[(2'-trifluoromethyl-1,1']-biphen-4-yl)methyl]tetrazole

The title compound was prepared via the method described previously. ¹ HNMR (DMSO-d6)δ: 5.85 (s, 2H); 7.10 to 8.25 (m, 12H). MS (ESI) 424.14 (M+H)⁺.

EXAMPLE 157 1-(3-aminocarbonylphenyl)-5-{[(2'-aminosulfonyl-[1,1']-biphen-4-yl)methyl}tetrazole

The title compound was prepared via the method described previously. ¹ M(DMSO-d6)δ: 5.85 (s, 2H); 7.15 to 8.25 (m, 12H). MS (ESI) 435.12 (M+H)⁺.

EXAMPLE 158 1-(3-amidinophenyl)-5-[(4'-cyclopentyloxyphenyl)aminocarbonyl]-3-methyl-pyrazole, Trifluoroacetic Acid Salt

Part A: Standard coupling protocol of 4-cyclopenyloxy-aniline (obtained by the displacement of 4-fluoronitrobenzene with the anion of cyclopentanol, followed by catalytic (10% Pd/C) reduction in methanol) with the acid chloride derived for N1-(3-cyanophenyl)-3-methyl-pyrazole-5-carboxylic acid afforded the amide precursor as a pale yellow oil; ¹ HNMR (CDCl₃) δ: 7.79 (bs, 1H), 7.75-7.50 (m, 7H), 6.95 (d, 1H), 6.85 (m, 1H), 4.75 (m, 1H), 1.95-1.70 (m, 6H), 1.60 (bm, 2H), 2.30 (m, 3H) ppm; ESI mass spectrum m/z (rel intensity) 387 (M+H, 100).

Part B: The title compound was obtained as colorless crystals after purification (via standard techniques) following the standard Pinner/amidine reaction sequence. ¹ HNMR (DMSO, d₆) δ: 10.39 (s, 1H), 9.42 (bs, 2H), 9.05 (bs, 2H), 7.94 (s, 1H), 7.82-7.68 (cp, 3H), 7.71 (d, 2H), 6.97 (s, 1H), 6.88 (d, 2H), 4.77 (m, 1H), 2.33 (s, 3H), 1.84-1.59 (cp, 8H) ppm; ESI mass spectrum m/z (rel intensity) 404.2 (M+H, 100).

EXAMPLE 159 1-(3-amidinophenyl)-5-[(3-((pyrid-2-yl)methylamino)phenyl) aminocarbonyl]-3-methyl-pyrazole, Trifluoroacetic Acid Salt

Part A: Standard coupling of 3-((pyrid-2-yl)methylamino)aniline [obtained in a two step sequence (condensation and reduction) from 3-nitroaniline and 2-pyridylcarboxaldehyde afforded the desired bis aniline derivative; ¹ HNMR (CDCl₃) δ: 8.58 (d, J=5.13, 1H); 7.67 (t, J=7.69, 1H); 7.35 (d, J=7.69, 1H); 7.19 (m, 1H); 6.99 (t, J=7.69, 8.06, 1H); 6.14 (m, 2H); 6.01 (m, 1H); 4.66 (brd, 1H); 4.44 (s, 2H); 3.56 (brd, 2H) ppm; Mass spectrum analysis (NH3-CI) 200 (M+H, 100)].

With the acid chloride derived from 1-(3-cyanophenyl)-3-methyl-pyrazole-5-carboxylic acid afforded the coupled benzonitrile precursor which was then subjected to the standard Pinner amidine reaction sequence to afford the desired benzamidine compound as colorless crystals; ¹ HNMR (DMSO) δ: 10.28 (s, 1H); 9.42 (s,2H); 9.08 (s, 2H): 8.58 (d, J=4.39, 1H): 7.83 (m, 3H); 7.72 (m, 2H); 7.46 (d, J=8.06, 1H); 7.40 (t, J=5.49, 6.59, 1H); 7.01 (m, 3H); 6.88 (d, J=8.05, 1H); 6.34 (d, J=8.06, 1H ); 4.39 (S. 2H): 2.31 (s, 3H) ppm; ESI mass spectrum analysis m/z (rel intensity) 426.1 (M+H, 100); HRMS for C₂₄ H₂₄ N₇ 0 426.204234 (calcd.), 426.201998 (obs).

EXAMPLE 160 1-(3-amidinophenyl)-3-methyl-5-[(4'-(N-imidazolyl)phenyl)aminocarbonyl]pyrazole

Part A. Preparation of N-(4-nitrophenyl)imidazole

4-Imidazolo-nitrobenzene (5 g) was hydrogenated (10% Pd/C) in 200 mL methanol for 20h. The reaction mixture was filtered through a celite pad and evaporated the solvent to afford 3.99 g of the crude product which was used directly in the next step. Mass spectrum analysis (H₂ O-GC/MS) :160 (M+H, 100).

Part B. Preparation of 1-(3-cyanophenyl)-3-methyl-5-[(4'-(N-imidazolyl)phenyl)aminocarbonyl]pyrazole

The product from part A was then coupled to 1-(3-cyanophenyl)-3-methylpyrazole-5-carboxylic acid via the acid chloride methodology described previously to afford the desired amide which was then purified via standard reverse phase HPLC techniques to afford the desired material. ¹ HNMR (DMSO-d6, 300 MHz) δ: 10.73 (s,1H) 9.35 (bs,1H) 8.13 (s,1H) 7.95 (s,1H) 7.90-7.60 (complex,8H) 7.0 (s,1H) 2.30 (s,3H) ppm; ESI mass spectrum analysis m/z (rel. intensity) 369 (m+H, 100); HRMS calc. mass 369.146384; found 369.145884.

Part C. Preparation of 1-(3-amidinophenyl)-3-methyl-5-[(4'-(N-imidazolyl)phenyl)aminocarbonyl]pyrazole

The product from part B was then subjected to the standard Pinner amidine reaction sequence to afford the desired benzamidine after HPLC purification. ¹ HNMR (DMSO-d6, 300 Mhz) δ: 10.65 (s,1H) 9.40 (bs,2H) 9.00 (bs,2H) 8.19 (s,1H) 7.90 (s,1H) 7.80-7.55 (complex,8H) 7.06 (s,1H) 7.00 (s,1H) 2.30 (s,3H) ppm; ESI mass spectrum analysis m/z (rel. intensity) 386 (M+H, 100). HRMS (FAB), calc. mass 386.172933; found 386.173388.

EXAMPLE 161 1-(3-amidinophenyl)-3-trifluoromethyl-5-[(4'-(N-morpholino)-3-chlorophenyl)aminocarbonyl]pyrazole

Part A. Preparation of 1-(3-cyanophenyl)-3-trifluoromethyl-5-[(4'-(N-morpholino)-3-chlorophenylaminocarbonyl]pyrazole

Standard coupling of commercially available 2-chloro-4-morpholinoaniline with N-(3-cyanophenyl)-3-trifluoromethyl-pyrazole-5-carboxylic acid via its acid chloride under usual conditions afforded the desired coupled product. ¹ HNMR (DMSO-d6, 300 MHz) δ: 10.66 (s,1H), 8.12 (s,1H), 7.97 (d,1H), 7.87 (d,1H), 7.70 (complex,3H), 7.50 (dd,1H), 7.14 (d,2H), 3.70 (m,4H), 2.90 (m,4H) ppm; ESI mass spectrum analysis m/z (rel. intensity) 476 (M+H, 100).

Part B: Preparation of 1-(3-amidinophenyl)-3-trifluoromethyl-5-((4'-N-morpholino)-3-chlorophenyl)aminocarbonyl)pyrazole

The cyano compound from part A was converted to the amidino derivative via the amidoxime as previously described. The amidoxime was reduced to the title compound (acetic acid/acetic anhydride and catalytic reduction of the acetate with 10% palladium on carbon under a hydrogen atmosphere) as previously described. The crude product was purified by standard HPLC technique to afford the desired compound as its bis TFA salt. ¹ HNMR (DMSO-d6, 300 MHz) δ: 10.73 (s,1H) 9.41 (bs,2H) 9.09 (bs,2H) 7.98 (s,1H) 7.89 (m,2H) 7.73 (complex,3H) 7.50 (d,1H) 7.14 (d,1H) 3.69 (complex,4H) 2.89 (complex,4H) ppm; ESI mass spectrum analysis m/z (rel. intensity) 493 (M+H, 100); HRMS(FAB+): calc-493.136662, obs. 493.136951.

EXAMPLE 162 1-(3-amidinophenyl)-3-methyl-5-[(4'-(N-pyrrolidinocarbonyl)-3'-chlorophenyl)aminocarbonyl]pyrazole

Part A: Preparation of 4'-pyrrolidinocarbonyl-3-chloronitrobenzene

To a dichloromethane solution of 4-nitro-3-chlorobenzoic acid (1.61 g) was added N-methylmorpholine (1.93 mL) and isobutylchloroformate (1.04 mL) followed by the addition of pyrrolidine (0.67 mL) and the reaction mixture was warmed to ambient temperature. Concentration of the reaction mixture followed by aqueous workup and extraction with ethylacetate afforded crude product which was used directly into the next reaction. LRMS(NH3-CI): 255 (m+H).

Part B. Preparation of 4'-(pyrrolidinocarbonyl)-3-chloroaniline

The crude 4'-(pyrrolidinocarbonyl)-3-chloronitrobenzene was treated with a catalytic amount 10% palladium on carbon in 20 mL methanol and placed under 10 psi hydrogen for 15h. Passed through a 1" Celite pad and concentrated filtrate. The residue was washed with ethyl acetate and 3×20 mL portions 1.0M HCl, dried (magnesium sulfate) and concentrated in vacuo. Recrystallized from methylene chloride/methanol to afford 1.80 g of crystalline 4'-carboxamidopyrrolindino-3-chloroaniline. ¹ HNMR (DMSO-d6, 300 MHz) δ: 6.94 (d,1H,J=8.42), 6.55 (d,1H,J=1.83), 6.47 (dd,1H,J=8.43,J=7.69), 3.36 (t,2H,J=6.23,J=6.95), 3.09 (t,2H,J=6.22,J=6.23), 1.78 (m,4H) ppm; Mass spectrum analysis (NH3-CI): 225 (m+H, 100).

Part C. Preparation of 1-(3-cyanophenyl)-3-methyl-5-[(4'-(pyrrolidinocarbonyl)-3-chlorophenyl)]aminocarbonyl)pyrazole

Standard coupling of the product from part B with the acid chloride derived from 1-(3-cyanophenyl)-3-methyl-pyrazole 5-carboxylic acid chloride afforded the desired coupled product. ¹ HNMR (DMSO-d6, 300 MHz) δ: 10.71 (s,1H), 7.97 (d,1H), 7.84 (m,2H), 7.76 (m,1H), 7.63 (m,2H), 7.32 (d,1H), 7.00 (s,1H), 3.42 (t,2H), 3.06 (t,2H), 2.29 (s,3H), 1.80 (m,4H) ppm; ESI mass spectrum analysis m/z (rel. intensity) 434 (M+Na, 100).

Part D. Preparation of 1-(3-amidinophenyl)-3-methyl-5-[(4'-pyrrolidinocarbonyl)-3-chlorophenyl)aminocarbonyl]pyrazole

The benzonitrile product from part C was then converted to the desired benzamidine via standard conditions described previously. Purification via reverse phase HPLC afforded the title compound as its trifluoro-acetate salt. ¹ HNMR (DMSO-d6, 300 MHz)δ: 10.73 (s,1H), 9.38 (s,2H), 9.04 (s,2H), 7.91 (s,1H), 7.85 (s,1H), 7.79 (d,1H), 7.74 (d,1H), 7.67 (d,1H), 7.62 (m,1H), 7.02 (s,1H), 3.41 (t,2H), 3.06 (t,2H), 2.30 (s,3H), 1.82 (m,4H) ppm; ESI mass spectrum analysis m/z (rel. intensity) 451 (M+H, 100). HRMS(CI): obs. 451.164788 calc.451.164927.

EXAMPLE 163 1-(3-amidinophenyl)-3-methyl-5-[(4'-(N-morpholinocarbonyl)-3-chlorophenyl)aminocarbonyl]pyrazole

Part A. Preparation of 4-(N-morpholinocarbonyl)-3-chloronitrobenzene

To a dichloromethane solution of 4-nitrobenzoyl chloride (2.41 g) was added morpholine (3.40 mL) in 75 mL methylene chloride at 0° C. The reaction mixture was warmed to ambient temperature over 20h, then diluted with water (100 mL). The organic layer was separated, washed with water (50 mL), 1.0M HCl (50 mL), dried (magnesium sulfate) and concentrated in vacuo. The crude material was used directly into the next step without further purification. Mass spectrum analysis (NH3-CI): 237 (m+H, 100). The product obtained above was then subjected to catalytic reduction (10% palladium on carbon in 60 mL methanol and placed under 60 psi hydrogen for 3h), filtered through a celite pad and evaporated to afford the desired aniline derivative. ¹ HNMR (DMSO-d6, 300 MHz) δ: 7.09 (d,2H), 6.50 (d,2H), 3.54 (t,4H), 3.44 (t,4H), 3.29 (S,2H) ppm; Mass spectrum analysis (NH3-CI): 207 (m+H, 100).

Part B. Preparation of 1-(3-cyanophenyl)-3-methyl-5-[4'-(N-morpholinocarbonyl)-3-chlorophenyl)aminocarbonyl]pyrazole

Standard coupling of the product from part A with the acid chloride derived from N-(3-cyanophenyl)-3-methylpyrazole-5-carboxylic acid followed by usual workup afforded the desired product after silica gel column chromatography (oil); HNMR (DMSO-d6, 300 MHz) δ: 10.63 (s,1H), 7.94 (s,1H), 7.83 (d,1H,J=7.69), 7.75 (dd,1H,J=8.06,J=8.06), 7.70 (d,2H,J=8.42), 7.63 (t,1H,J=7.69,J=8.05), 7.37 (d,2H,J=8.06), 6.98 (s,1H), 3.28 (d,8H,J=6.96), 2.28 (s,3H); ESI mass spectrum analysis m/z (rel. intensity) 438 (M+Na), 416 (M+H, 100).

Part C. Preparation of 1-(3-amidinophenyl)-3-methyl-5-[(4'-(N-morpholinocarbonyl)phenyl)aminocarbonyl]pyrazole

Standard conversion of the product from part B to the benzamidine afforded after purification via reverse phase HPLC the desired product. ¹ HNMR (DMSO-d6, 300 MHz) δ: 10.66 (s,1H), 9.38 (bs,2H), 9.04 (bs,2H), 7.90 (d,1H,J=9.52), 7.78 (d,1H,J=7.33), 7.73-7.62 (complex,4H), 7.37 (d,2H,J=8.42,) 7.00 (s,1H), 3.55-3.46 (complex,8H), 2.30 (s,3H). ESI mass spectrum analysis m/z (rel. intensity) 433 (M+H, 100); HRMS obs. 433.199045; calc.433.198814.

EXAMPLE 164 1-(3-Cyanophenyl)-5-[(4'-(N-imidazolyl)phenyl)aminocarbonyl]-3-trifluoromethylpyrazole, Trifluoroacetic Acid

1-(3-Cyanophenyl)-3-trifluoromethyl-pyrazol-5-yl carboxylic acid (0.5 g, 1.8mmol) was coupled with 4-imidazoyl aniline (0.3 g, 1.8 mmol) by standard conditions and purified by HPLC to afford 0.67 g (71%) product. ¹ HNMR (DMSO-d₆) δ: 10.99 (s,1H), 9.55 (s,1H), 8.22 (d, j=5.49 Hz, 2H), 8.04 (d, j=7.69 Hz, 1H), 7.96 (d,j=8.06 Hz, 1H), 7.89 (s+d, j=8.79 Hz, 3H), 7.80 (m,4H) ppm; HRMS 423.118119 (calc'd), 423.116015 (obs.); Analysis calc'd for C₂₁ H₁₃ F₃ N₆ O(TFA) C:51.50,H:2.63,N:15.67, found C:51.52,H:2.71,N:15.49.

EXAMPLE 165 1-(3-amidinophenyl)-5-[(4'-(N-imidazolyl)phenyl)aminocarbonyl]-3-trifluoromethylpyrazole, Trifluoroacetic Acid

1-(3-Cyanophenyl)-5-[(4'-imidazol-1-ylphenyl) aminocarbonyl]-3-trifluoromethylpyrazole was subjected to standard Pinner amidine reaction sequence and purified under standard conditions to afford title amidine (79%). ¹ HNMR (DMSO-d₆)δ: 11.02 (s,1H), 9.46 (s,1.5H),9.42 (s.1H), 9.22 (s,1.5H), 8.17 (s,1H), 8.06 (s,1H), 7.97 (t,j=7.69 Hz, 2H), 7.88 (d, j=8.79 Hz, 2H), 7.80 (m,3H), 7.79 (d, j=9.0 Hz, 2H) ppm; HRMS 440.144668 (calc'd), 440.144557 (obs.); Analysis calc'd for C₂₁ H₁₆ F₃ N₇ O (TFA)2 (H₂ O)1: C:43.81,H:2.94,N:14.30,found C:43.76,H:2.70,N:13.95.

EXAMPLE 166 1-(3-amidinophenyl)-5-[(4'-(N-methyltetrazolon-1-yl) phenyl)aminocarbonyl]-3-trifluoromethylpyrazole, Trifluoroacetic Acid

Part A. 4-Nitrobenzoic acid was converted to the 4-nitrophenyltetrazolone according to the procedure of Toselli, M. and Zaneratio, P., J.C.S. Perk. Trans. 1992, 1, 1101. ¹ HNMR (DMSO-d₆) δ: 8.46 (d, j=9.15 Hz, 2H), 8.22 (d, j=9.16 Hz, 2H).

Part B. To 4-nitrophenyltetrazolone (0.8 g, 3.9 mmol) in DMF (10 mL) at 0° C. was added iodomethane (0.38 mL) and 60% sodium hydride (0.23 g). The reaction was allowed to warm to ambient temperature and stirred 24h. The reaction was quenched with water and extracted with ethyl acetate and dried (MgSO₄). The crude product was purified by chromatogaphy on silica gel and recyrstallized from methylene chloride/hexanes to afford 0.35 g (41%) product, MS (DCI) m/z 192 (M+H-NO)⁺, 209 (M+NH₄ -NO)⁺.

Part C. The nitro compound (0.215 g, 0.97 mmol) from part B was hydrogenated under 1 atmosphere of hydrogen in the presence of a catallytic amount of 10% palladium on carbon to the aniline, Mass spectrum analysis (DCI) m/z 192 (M+H)⁺, 209 (M+NH4)⁺.

Part D. 1-(3-Cyanophenyl)-3-trifluoromethyl-pyrazol-5-yl carboxylic acid (0.38 g, 1.4 mmol) was coupled with the aniline from part C by standard procedure to afford the nitrile in 43% yield. ¹ HNMR (CDCl₃) δ: 8.04 (s,1H), 7.95 (d, j=9.16 Hz, 2H), 7.85 (s,1H), 7.79 (m,2H), 7.67 (m,3H), 7.21 (s,1H), 3.71 (s,3H) ppm; MS (ESI) m/z=454.9 (M+H)⁺, 477 (M+Na)⁺.

Part E. The nitrile from part D was subjected to the standard Pinner conditions to afford the title amidine in 53% yield. ¹ HNMR (DMSO-d₆) δ: 10.93 (s,1H), 9.46 (s,1.5H), 9.12 (s,1.5H), 8.04 (s,1H), 7.95 (d, j=7.69 Hz, 2H), 7.84 (s,4H), 7.81 (m,2H), 3.61 (s,3H) ppm; HRMS 472.145731 (calc'd), 472.145205 (obs.); Analysis calcd for C₂₀ H₁₆ F₃ N₉ O₂ (TFA)1.2: C:44.23,H:2.85,N:20.73,found C:44.40, H:2.85, N:20.15.

EXAMPLE 167 1-(3'-Aminocarbonylphenyl)-5-(2'-aminosulfonylphenyl-[1,1']-biphen-4-yl)methylcarbonyl]-3-methyl-pyrazole

The title amide was isolated from the Pinner reaction via HPLC separation protocols. ¹ HNMR (DMSO-d₆) δ: 10.63 (s,1H), 8.06 (s,1H), 8.03 (dd, j=2.19, 7.32 Hz, 1H), 7.87 (s,1H), 7.61 (m,2H), 7.53 (m+d,j=7.33 Hz, 3H), 7.44-7.26 (m,6H), 7.21 (s,2H), 4.33 (s,2H), 2.33 (s,3H) ppm; ESI mass spectrum analysis m/z (rel. intensity) 497 (M+Na, 100) 433 (M+H).

EXAMPLE 168 1-(3-amidinophenyl)-5-[4'-(pyrrolidinomethyl)phenyl) aminocarbonyl]-3-methyl-pyrazole, Trifluoroacetic Acid Salt

Standard coupling of 4-(pyrrolidinomethyl)aniline with the acid chloride derived from 1-(3-cyanophenyl)-3-methyl-pyrazole-5-carboxylic acid afforded the coupled benzonitrile precursor which was then subjected to the standard Pinner amidine reaction sequence to afford after purification the title compound as colorless crystals; ¹ HNMR (DMSO) δ: 10.69 (s, 1H); 9.42 (s, 2H); 9.20 (s, 2H); 7.96 (s, 1H); 7.84 (m, 1H); 7.75-7.68 (m, 4H); 7.48 (d, 2H, J=8.79); 7.04 (s, 1H); 4.31 (m, 2H); 3.35 (brd, 2H); 3.05 (brd, 2H); 2.34 (S, 3H); 2.05 (brd, 2H); 1.85 (brd, 2H) ppm; ESI mass spectrum m/z (rel. intensity) 403 (M+H, 100); HRMS found for C₂₃ H₂₇ N₆ O 403.224635 (calcd), 403.222719 (obs).

EXAMPLE 169 1-(3-aminophenyl)-3-methyl-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole

Part A: To commercially available 3-nitrophenylhydrazine hydrochloride (1.00 g, 5.27 mmol) in 15 mL of absolute ethanol was added 1,1,1-trichloro-4-methoxy-3-penten-2-one (1.15 g, 5.27 mmol) and the reaction brought to reflux for 12 h. The solvent was evaporated and the residue subjected to silica gel flash chromotography eluting with 20% ethyl acetate in hexanes. The first fraction to elute was the desired ethyl (3-nitrophenyl)-3-methyl-5-pyrazole carboxylate. MS (ES+) 276.1 (M+H)⁺ (100%). The ester (110 mg, 0.400 mmol) was coupled with (2'-tert-butylaminosulfonyl-[1,1']-biphen-4-yl)amine (122 mg, 0.400 mmol) using Weinreb's trimethylaluminium procedure. After preparative TLC (eluent 50% ethyl acetate/hexanes) 178.2 mg (83% yield) of 1-(3-nitrophenyl)-3-methyl-5-[(2'-tert-butylaminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole was isolated as a colorless solid. MS (ES+) 551.24 (M+NH₄)⁺ (30%); 556.18 (M+Na)⁺ (100%).

Part B: The product from part 170.5 mg (0.320 mmol) was refluxed in 5 mL of trifluoroacetic acid for 12 h. Preparative TLC (eluent 10% methanol/chloroform) afforded 1-(3-nitrophenyl)-3-methyl-5-[(2'-butylaminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole as a colorless solid. MS (ES+) 478.23 (M+H)⁺ (30%); 500.21 (M+Na)⁺ (100%). HRMS (FAB+)(M+H)⁺ : calc. 478.118516; found 478.117673.

Part C: The product from part B 64.3 mg (0.135 mmol) was subjected to catalytic hydrogenation (5% Pd/C in ethanol under 1 atm of hydrogen) to afford the title compound as a colorless solid. ¹ HNMR (CD₃ OD) δ: 8.08 (d, J=7.7 Hz, 1H), 7.61-7.30 (m, 8H), 7.13 (t, J=7.7 Hz, 1H), 6.72 (m, 3H), 2.33 (s, 3H). MS (ESI+): 448.11 (M+H)⁺ (35%); 470.16 (M+Na)⁺ (100%). HRMS (FAB+)(M+H)⁺ : calc. 448.144337; found 448.144965.

EXAMPLE 170 1-(2'-Aminophenyl)-3-methyl-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole

The title compound was made in a similar manner to Example 169. ¹ HNMR (CD₃ OD)δ: 8.14-8.03 (m, 2H), 7.58-6.74 (m, 11H), 2.47 (s, 3H). MS (ES+) 448.12 (M+H)⁺ (60%); 470.16 (M+Na)⁺ (100%).

EXAMPLE 171 1-(3-amino-4'-chlorophenyl)-3-methyl-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole

The title compound was made in a similar manner to Example 169. ¹ HNMR (CD₃ OD)δ: 8.08 (d, J=6.9 Hz, 1H), 8.07-7.23 (m, 8H), 6.91 (d, J=2.2 Hz, 1H), 6.75 (s, 1H), 6.66 (dd, J=8.43, 2.56 Hz, 1H), 2.33 (s, 3H). MS (ES+) 482.0 (M+H)⁺ (80%); 484.0 (30%); 504.0 (M+Na)⁺ (100%); 506.0 (40%).

EXAMPLE 172 1-(3-amino-4'-fluorophenyl)-3-methyl-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole

The title compound was made in a similar manner to Example 169. ¹ HNMR (CD₃ OD) δ: 8.14-8.03 (m, 2H), 7.58-6.74 (m, 11H), 2.47 (s, 3H). MS (ES+) 466.0 (M+H)⁺ (5%); 488.0 (M+Na)⁺ (100%).

EXAMPLE 173 1-(3-amino-4'-methoxyphenyl)-3-methyl-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl) aminocarbonyl]pyrazole

The title compound was made in a similar manner to Example 169. ¹ HNMR (CD₃ OD)δ: 8.10 (d, J=6.6 Hz, 1H), 7.63-7.31 (m, 7H), 6.89-6.72 (m, 4H), 3.88 (s, 3H), 2.34 (s, 3H). MS (ES+) 478.1 (M+H)⁺ (25%); 500.0 (M+Na)⁺ (100%).

EXAMPLE 174 1-(3-amino-4'-chlorophenyl)-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]tetrazole, Trifluoroacetic Acid Salt

Part A. Preparation of 1-(3-nitro-4-chlorophenyl)-5-carboethoxytetrazole

4-Chloro-3-nitroaniline (10.36 g, 60 mmol) was dissolved in CH₂ Cl₂ (100 mL). Triethylamine (10 mL, 70 mmol) was added followed by ethyl oxalyl chloride (6.8 mL, 60 mmol). The mixture was stirred at room temperature under N₂ for 15 min. It was diluted with CH₂ Cl₂ and washed with water and brine. The CH₂ Cl₂ solution was dried over MgSO₄ and concentrated to a light yellow solid (15.53 g).

The above amide (5.5 g, 20.2 mmol) was refluxed 4 h with a solution of triphenylphosphine (7.87 g, 30 mmol) in 100 mL of CCl₄. (The solution was stirred at 0° C. for 15 min before the amide was added). The reaction mixture was cooled and the precipitate was filtered off. The filtrate was concentrated to a solid. It was then dissolved in 100 mL of CH₃ CN and NaN₃ (1.31 g, 1 eq) was added. The mixture was stirred at room temperature under N₂ for 12 h. The solvent was removed. The solid was dissolved in EtOAc and washed with water and brine. It was dried over MgSO₄, concentrated, and chromatographed on silica gel (CH₂ Cl₂) to afford 3.19 g of the desired product. ¹ HNMR (CDCl₃)δ: 1.35 (t, 3H); 4.42 (q, 2H); 7.50-7.70 (m, 2H); 8.10 (s, 1H). MS (DCI-NH₃) 315 (M+NH₄)+.

Part B. Preparation of 1-(3-nitro-4-chlorophenyl)-5-[(2'-t-butylaminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]tetrazole

2'-t-Butylaminosulfonyl-4-amino-[1,1']-biphenyl (1.33 g, 4.37 mmol) was dissolved in 40 mL of anhydrous CH₂ Cl₂, and trimethylaluminum (11 mL of 2.M solution in heptane) was added slowly. The mixture was stirred at room temperature under N₂ for 15 min. Then, a solution of material from part A (1.30 g, 4.37 mmol) in anhydrous CH₂ Cl₂ (40 mL) was added. The mixture was stirred at room temperature under N₂ for 18 h. The reaction mixture was quenched carefully with 1N HCl. It was diluted with CH₂ Cl₂ and washed with water and brine. The organic solution was then dried over MgSO₄, concentrated, and chromatographed on silica gel (CH₂ Cl₂) to give 1.5 g of the desired product. MS(ESI) 554.1 (M-H)⁺.

Part C. Preparation of 1-(3-nitro-4-chlorophenyl)-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]tetrazole

The material from Part B (1.5 g, 2.7 mmol), and trifluoroacetic acid (20 mL) was stirred at room temperature under N₂ overnight. The trifluoroacetic acid was removed and chromatographed on silica gel (10% EtOAc/CH₂ Cl₂) to afford 0.72 g of desired product. ¹ HNMR (DMSO-d6)δ7.25 to 8.20 (m, 11H); 8.69 (s, 1H); 11.55 (s, 1H). MS (ESI) 497.9:499.9 (3:1) (M-H)⁺.

Part D. Preparation of 1-(3-amino-4-chlorophenyl)-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]tetrazole, Trifluoroacetic Acid Salt

The material from part C (0.72 g, 1.44 mmol) was dissolved in EtOAc (30 mL). SnCl₂ 2H₂ O (2.59 g, 11.52 mmol) was added. The reaction mixture was brought to reflux for 1 h and then cooled it to the room temperature. Saturated NaHCO₃ was added to the mixture until the pH 8.0. The mixture was partitioned between EtOAc and NaHCO₃ layer. The EtOAc layer was washed with water and brine. It was dried over MgSO₄ and concentrated. The solid was dissolved in CH₃ CN/TFA and purified by reversed phase HPLC to give 300 mg of the desired product. ¹ HNMR (DMSO-d6)δ: 6.80 to 8.00 (m, 11H); 11.40 (s, 1H). MS (DCI-NH₃) 470.0 (M+H)⁺.

EXAMPLE 175 1-1-(3-amino-4'-chlorophenyl)-5-{[(2'-amainosulfonylphenyl)pyridin-2-yl]aminocarbonyl}tetrazole, Trifluoroacetic Acid Salt

The title compound was prepared via the method of Example 171. ¹ HNMR (DMSO-d6)δ: 6.80 to 8.40 (m, 10H); 11.70 (s, 1H). MS (ESI) 471.20 (M+H)⁺.

EXAMPLE 176 1-(3-amino-4'-methoxyphenyl)-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]tetrazole, Trifluoroacetic Acid Salt

The title compound was prepared via the method of Example 174. ¹ HNMR (DMSO-d6)δ: 6.80 to 8.05 (m, 1H); 11.15 (s, 1H). MS (ESI) 466.0 (M+H)⁺.

EXAMPLE 177 1-(3-aminomethylphenyl)-5-[(2'-aminosulfonylphenyl)pyrid-2-yl) aminocarbonyl]-3-methylpyrazole, Trifluoroacetic Acid

Part A: Ethyl-1-(3-cyanophenyl)-3-methyl-5-pyrazole-carboxylate (2.7 g, 10.58 mmol) was dissolved in methanol (50 mL). To this solution was added glacial acetic acid (2 mL) and 10% palladium on carbon (cat.). The reaction mixture was hydrogenated (50 psi) for 12h, filtered over celite and evaporated to the crude benzylamine salt. Without further purification the crude amine was converted to the carbo-benzyloxy derivative by treatment with CBzCl in saturated sodium bicarbonate solution. The organics were extracted with ethyl acetate (2×100 mL) dried over magnesium sulfate and evaporated to the crude product (2.15 g obtained). The oil was then hydrolysed with LiOH (0.22 g, 5.5 mmoL) in aqueous THF for 16h. The reaction mixture was quenched with water (500 mL) and unreacted products were extracted with ethyl acetate (2×100 mL). The aqueous layer was carefully acidified (1 NHCl) followed by extraction with ethyl acetate (2×100 mL) dried (magnesium sulfate) and evaporated to pure acid (1.23 g); ESI(-ve) 362 (M-H, 100).

Part B: Standard coupling (TBTU, triethylamine in anhydrous THF) of the product from part A with 2-amino-5-(2'-tert-butylaminosulfonylphenyl)pyridine afforded the desired amide derivative which was dehydrogenated (10% Pd/C, methanol, balloon) overnight. The reaction mixture was filtered over celite and evaporated to a pale yellow oil. The desired product was obtained as colorless crystals after purification via standard reverse phase techniques; ¹ HNMR (DMSO-d₆) δ: 8.35 (d, 1H), 8.19 (bs, 1H), 8.00 (t, 1H), 7.78 (dd, 1H), 7.63 (t, 2H), 7.77-7.37 (m, 6H), 7.06 (s, 1H), 4.13 (m, 2H), 2.30 (s, 3H) ppm; ESI mass spectrum analysis m/z (rel intensity) 463.3 (M+H, 100).

EXAMPLE 178 1-(3-aminomethyl-4'-methylphenyl)-5-[(2'-aminosulfonyl-[1,1']-biphien-4yl)aminocarbonyl]-3-methyl-pyrazole, Trifluoroacetic Acid Salt

Part A: Ethyl 1-(3-cyano-4-methylphenyl)-3-methyl-5-pyrazole-carboxylate was prepared as colorless crystals following the standard condensation (3-cyano-4-methylphenyl-hydrazine and ethyl 2-(N-(methoxy)imino)-4-oxopentanoate in acetic acid) reaction protocol discussed previously. ¹ HNMR (CDCl₃) δ: 7.68 (s, 1H), 7.57 (dd, 1H), 7.58 (d, 1H), 6.82 (s, 1H), 4.24 (q, 2H), 2.40 (s, 3H0, 2.37 (s, 3H), 1.27 (t, 3H) ppm; ESI mass spectrum analysis (270 (M+H, 100).

Part B: Standard Weinreb coupling protocol of the product from part A with 1-amino-2'-tert-butylaminosulfonyl-biphenyl afforded the desired coupled product. ¹ HNMR (CDCl₃) δ: 8.30 (bs, 1H), 8.13 (bd, 1H), 7.78-7.23 (m, 10H), 6.78 (s, 1H), 3.68 (s, 1H), 2.60 (s, 3H), 2.40 (s, 3H0, 1.01 (s, 9H) ppm; ESI mass spectrum analysis ESI mass spectrum m/z (rel intensity) 550 (M+Na, 100).

Part C: The product from part B was then hydrogenated at 50 psi in acidic methanol as previously described, then treatment with TFA (neat) and purified via standard reverse phase chromatography to afford the title compound as colorless crystals. ¹ HNMR (DMSO, d₆) δ: 10.6 (s, 1H), 8.14 (bs; 2H), 8.01 (d, 1H), 7.68 (d, 2H), 7.54 (m, 2H), 7.26 (m, 5H), 6.91 (s, 1H), 4.07 (bd, 2H), 2.38 (s, 3H), 2.33 (s, 3H) ppm; ESI mass spectrum m/z (rel intensity) 476 (M+H, 100).

EXAMPLE 179 1-(3-aminomethyl-4'-fluorophenyl)-5-[(2'-aminosulfonyl-[1,1']-biphen-4yl)aminocarbonyl]-3-methyl-pyrazole, Trifluoroacetic Acid Salt

The title benzylamine was obtained from 3-cyano-4-fluorophenyl hydrazine via methods described previously. ¹ HNMR (DMSO, d₆) δ: 8.25 (bs, 3H), 8.00 (d, 1H), 7.78-7.23 (cp, 12H), 6.95 (s, 1H), 4.14 (m, 2H), 2.30 (s, 3H) ppm; ESI mass spectrum m/z (rel intensity) 480 (M+H, 100).

EXAMPLE 180 1-(3-aminomethylphenyl)-5-[(4'-(N-pyrolidino-carbonyl)phenyl)aminocarbonyl]-3-trifluoromethylpyrazole, Trifluoroacetic Acid

Part A. Preparation of 1-(3-cyanophenyl)-5-[(4'-(N-pyrrolidinocarbonyl)phenyl)aminocarbonyl]-3-trifluoromethylpyrazole.

1-(3-Cyanophenyl)-3-trifluoromethyl-pyrazol-5-yl carboxylic acid (0.5 g, 1.8 mmol) was coupled with 4-(N-pyrrolidinocarbonyl)aniline (0.3 g, 1.8 mmol) by standard conditions to afford 0.4 g (56%) of a white solid. ¹ HNMR (CDCl₃) δ: 9.72 (s,1H), 7.78-7.72 (m,4H), 7.61 (t, j=7.69 Hz, 1H), 7.23 (s, 4H), 3.67 (t, j=6.59 Hz, 2H), 3.43 (t, j=6.59 Hz, 2H), 1.98 (q, j=6.23 Hz, 2H), 1.89 (q, j=6.23 Hz, 2H) ppm; ESI mass spectrum analysis m/z (rel. intensity) 476 (M+Na, 100), 454.1 (M+H).

Part B. The nitrile from part A (0.4 g, 0.88 mmol), 10% palladium on carbon (50 mg) and ethanol (20 mL) was placed in a Parr apparatus and hydrogenated 18h at 40 psi. The reaction was filtered and concentrated. The crude product was purified by reverse phase HPLC and freeze-dried to afford 0.38 g (76%) of the title amine. ¹ HNMR (DMSO-d₆) δ: 10.91 (s,1H), 8.23 (brd s,2H), 7.73 (m,3H), 7.71 (d, j=8.79 Hz, 2H), 7.59 (m,2H), 7.54 (d, j=8.42 Hz, 2H), 4.16 (d, j=5.50 Hz, 2H), 3.45 (q, j=7.32 Hz, 4H), 1.83 (brd m, 4H) ppm; Analysis calc'd for C₂₃ H₂₂ F₃ N₅ O₂ (TFA)1 (H₂ O) 0.5: C:51.73, H:4.17, N:12.06, found C:51.45, H:3.95, N:11.73.

EXAMPLE 181 1-(3-Ethylcarboxyamidinophenyl)-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)-aminocarbonyl]-3-methyl Pyrazole

To 1-(3-cyanophenyl)-5-[(2'-t-butylaminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-methylpyrazole (88 mg, 0.15 mmol) in DMF (5 mL) was added ethyl chloroformate (0.017 mL, 0.17 mmol) and triethylamine (0.052 mL, 0.037 mmol) and the reaction was stirred 72h. The mixture was diluted with ethyl acetate and washed successively with water and brine and dried (MgSO₄). Purification by chromatography on silica gel using 3-10% methanol/methylene chloride as eluent afforded 27 mg (33%) of the title compound. ¹ HNMR (DMSO-d₆) δ: 10.62 (s,1H), 9.18 (s,1H), 8.16 (s,1H), 8.05 (m,2H), 7.70 (d,2H), 7.60 (5H,m), 7.37 (d,2H), 7.30 (d,1H), 7.24 (s,2H), 6.95 (s,1H), 4.10 (q,2H), 2.35 (s,3H), 1.20 (t,3H) ppm; HRMS 547.176365 (calcd), 547.178880 (obs.).

EXAMPLES 182 AND 183 1-(3-(1'-imino-1'-(N-morpholino))methyl)phenyl)-5-[(2'-tert-butylaminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-methylpyrazole, Trifluoroacetic Acid Salt and 1-(3-(1'-imino-1'-(N-morpholino))methyl)phenyl)-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-methyl-pyrazole, Trifluoroacetic Acid Salt

Part A: The morpholino amidine compound was prepared from the precursor nitrile via the standard Pinner reaction protocol, with anhydrous morpholine as the nucleophile. Standard HPLC purification then afforded the desired morpholino amidine compound as colorless crystals; ¹ HNMR (DMSO) δ: 11.39 (s, 1H) 9.67 (s, 1H); 9.27 (s, 1H); 8.62 (s, 2H); 8.09 (d, J=7.69, 1H); 7.79 (s, 1H); 7.73-7.61 (m, 5H); 7.42 (d, J=7.32, 1H); 7.30 (s, 1H); 7.08 (s, 1H); 3.81 (brd, 2H); 3.74 (brd, 2H); 3.63 (brd, 2H); 3.37 (brd, 2H): 2.31 (s, 3H); 1.04 (s, 9H) ppm; ESI mass spectrum analysis m/z (rel intensity) 603.2 (M+H, 100).

Part B: Removal of the tert-butyl group was then effected by heating the product from part A in TFA, followed by standard HPLC purification techniques afforded the desired morpholino amidine compound as colorless crystals; ¹ HNMR (DMSO) δ: 11.38 (s, 1H): 9.67 (s, 1H): 9.27 (s, 1H); 8.65 (s, 2H); 8.08 (m, 1H): 7.78 (s, 1H): 7.73-7.67 (m, 5H); 7.62 (m, 1H); 7.55 (s, 1H); 7.45 (m, 1H); 7.09 (s, 1H); 3.81 (brd, 2H); 3.74 (brd, 2H); 3.62 (brd, 2H); 3.37 (brd, 2H); 2.31 (s, 3H) ppm; ESI mass spectrum analysis m/z (rel intensity) 547.0 (M+H, 100). HRMS for C₂₆ H₂₇ N₈ O₄ S 547.187599 (calcd), 547.186294 (obs).

EXAMPLE 184 1-[3-[N-((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxycarbonyl)amidino]phenyl]-5-((2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl)-3-methylpyrazole

Part A. To 4-hydroxymethyl-5-methyl-1,3-dioxol-2-one (0.227 g, 1.75 mmol) (Alpegiani, M. et al, Syn. Com. 1992, 22 (9), 1277) in chloroform (5 mL) at 0° C. was added pyridine (0.15 mL) and 4-nitrophenyl chloroformate (0.387 g, 1.9 mmol). The reaction was allowed to warm to ambient temperature and was stirred 18h.

The reaction mixture was washed with water, brine and dried (Na₂ SO₄). The crude dioxolone was used in the next step.

Part B. To 1-(3-amidinophenyl)-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-methylpyrazole (80 mg, 0.14 mmol) in DMF (1 mL) was added the dioxolone from part A and triethylamine (0.038 mL). The reaction was stirred 18h. The reaction was diluted with ethyl acetate and washed with water and dried (MgSO₄). Purification by chromatography on silica gel using 3-5% methanol in methylene chloride afforded 47 mg (55%) of the title dioxolone. ¹ HNMR (DMSO-d₆) δ: 10.63 (s,1H), 8.25 (s,1H), 8.05 (t,2H), 7.62 (d,2H), 7.50 (m,5H), 7.37 (m,4H), 7.25 (s,2H), 6.93 (s,1H), 4.92 (s,2H), 2.37 (s,3H), 2.15 (s,3H) ppm; HRMS 631.161109 (calcd), 631.160927 (obs.).

EXAMPLE 185 1-(Pyrid-2-yl)-3-methyl-5-[(3-fluoro-2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole

The title compound was prepared by previously described methodology using 2-pyridine hydrazine·HCl. LRMS (M+H)⁺ m/z: 452.

EXAMPLE 186 1-(6-Bromopyridin-2-yl)-3-methyl-5-[(3-fluoro-2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole

By using previously described methodology, ethyl 3-methyl-1-(pyridin-2-yl)-1H-pyrazolecarboxylate was obtained. This compound was then treated with N-bromosuccinamide according to the following procedure.

A mixture of 3-methyl-1-(pyridin-2-yl)-1H-pyrazolecarboxylic acid (7.0483 mmol, 1.63 g) and N-bromosuccinimide (2.51 g, 2.0 eq.) in carbon tetrachloride (40 mL) was stirred at ambient temperature for 18 h. The reaction mixture was filtered through celite to remove solid impurity and washed with carbon tetrachloride (30 mL). The filtrate was evaporated and purified by flash chromatography on a silica gel column (200 g) eluted with 3:1 hexane:ethyl acetate to give 0.258 g of pure 3-methyl-1-(6-bromopyridin-2-yl)-1H-pyrazolecarboxylic acid (12%).

Thereafter, following previously described procedures the acid chloride of 3-methyl-1-(6-bromopyridin-2-yl)-1H-pyrazolecarboxylic acid was coupled with 3-fluoro-4-((2-N-t-butylsulfonamido)phenyl)aniline, and t-butyl protecting group removed with refluxing trifluoroacetic acid to obtain the title compound; LRMS (M+H)⁺ m/z: 530.

EXAMPLE 187 1-(3-amino-4-chlorophenyl)-5-[(2'-aminosulfonyl-3-chloro-[1,1']-biphen-4-yl)aminocarbonyl]tetrazole, Trifluoroacetic Acid Salt

The title compound was prepared by the same method described in Example 174. ¹ HNMR (DMSO-d₆)δ: 10.90 (s, 1H); 8.02 (d, 1H); 7.78 (d, 1H); 7.62 (m, 2H); 7.55 (s, 1H); 7.26-7.34 (m, 5H); 7.03 (s, 1H); 6.81 (d, 1H), 5.89 (bs, 2H). High resolution mass spectrum analysis: cald 504.0412, found 504.0411.

EXAMPLE 188 1-(3-amino-4-chlorophenyl)-5-[(4'-(1-pyrrolidinocarbonyl)phenyl)aminocarbonyl]tetrazole, Trifluoroacetic Acid Salt

The title compound was prepared by the same method described in Example 174. ¹ HNMR (DMSO-d₆)δ: 11.26 (bs, 1H); 7.80 (t, 1H); 7.49 (d, J=11.0 Hz, 1H); 7.42 (d, J=8.4 Hz, 1H); 7.40 (d, J=8.1 Hz, 1H); 7.04 (d, J=2.6 Hz, 1H); 6.79 (dd, J=8.4 and 2.6 Hz, 1H); 3.45 (t, J=6.2 Hz, 2H), 3.40 (t, J=5.8 Hz, 2H), 1.85 (m, 4H). ESI mass spectrum analysis m/z (relative intensity): 430.0 (M+H)⁺ ; 452.0, (M+Na)⁺.

EXAMPLE 189 1-(3-aminomethylphenyl)-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]tetrazole, Trifluoroacetic Acid Salt

1-(3-cyanophenyl)-5-[2'-(t-butylaminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]tetrazole prepared as shown in Part B of Example 24 (0.20 g, 0.40 mmol) was dissolved in 10 mL of EtOAc and 10 mL of EtOH. TFA (1 mL) and Palladium on carbon (10%) were added. The mixture was hydrogenated at 30 psi for 18 h. The reaction mixture was filtered through celite and washed with EtOAc. The filtrate was concentrated to a brown oil. It was dissolved in 5 mL of TFA and refluxed under N₂ for 30 minutes. The solvent was removed in vacuo and the resulting material was purified by reversed phase HPLC to give 59.8 mg of the title compound with 98% purity. ¹ HNMR (DMSO-d₆)δ: 11.54 (s, 1H); 8.25 (bs, 3H); 8.02 (d, J=6.3 Hz, 1H); 7.84 (bs, 1H); 7.77 (t, J=5.8 Hz, 2H); 7.72 (t, J=6.9 Hz, 2H); 7.60 (m, 2H); 7.39 (d, J=8.8 Hz, 2H), 7.32 (m, 1H), 7.31 (s, 2H), 4.18, (bs, 2H). ESI mass spectrum analysis m/z (relative intensity): 450.2 (M+H, 100)⁺.

EXAMPLE 190 1-(3-aminomethylphenyl)-5-[(2'-aminosulfonyl-3-fluoro-[1,1']-biphen-4-yl)aminocarbonyl]tetrazole, Trifluoroacetic Acid Salt

The title compound was prepared by the same method described in Example 189. ¹ HNMR (DMSO-d₆)δ: 11.28 (s, 1H); 8.23 (bs, 3H); 7.99 (d, J=6.6 Hz, 1H); 7.80 (bs, 1H); 7.70 (m, 2H); 7.60 (m, 2H); 7.41 (s, 2H); 7.31 (d, J=9.5 Hz, 2H), 7.20 (d, J=8.1 Hz, 1H), 4.14, (m, 2H). ESI mass spectrum analysis m/z (relative intensity): 467.9, (M+H, 100)⁺.

EXAMPLE 191 1-(3-aminomethylphenyl)-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]imidazole, Trifluoroacetic Acid Salt

Part A: A solution of 3-amino-benzonitrile (6.3 g, 53.4 mmol) in ethyl alcohol (50 mL) was treated with n-butyl glyoxylate (7.0 g, 53.8 mmol). After stirring for 18h at rt, the reaction mixture was concentrated at reduced pressure. The residue was purified by flash-chromatography (hexane/ethyl acetate, 1:1) affording an imine (4.0 g, 33%) as a colorless oil. ESI mass spectrum analysis m/z (relative intensity): 232 (M+H, 100).

Part B: To the solution of the imine from part A (1.6 g, 6.9 mmol) in methyl alcohol (10 mL) was added potassium carbonate (1.9 g, 13.9 mmol) and tosylmethyl isocyanate (2.3 g, 11.8 mmol). The solution was stirred for 1h at rt, then solvent was removed under reduced pressure. The residue was treated with the saturated sodium chloride solution and the mixture was extracted with methylene chloride. The organic extract was concentrated and triturated with methyl alcohol. The precipitate was collected and dried to afford the desired methyl 1-(3-cyanophenyl)-imidazole-5-carboxylate (1.5 g, 94%). ESI mass spectrum analysis m/z (relative intensity): 227 (M+H, 100).

Part C: A solution of (2'-tert-butylaminosulfonyl-[1-1']-biphen-4-yl)amine (3.5 mmol) in methylene chloride (3 mL) was treated dropwise with AlMe3 (2M in hexanes, 1.8 mL, 3.5 mmol). The resultant reaction mixture was stirred for 0.5h at rt, then treated with the product from part B (0.16 g, 0.7 mmoL) and allowed to stir for 18h. The mixture was carefully quenched with 10% HCl, extracted with methylene chloride, dried over magnesium sulfate and concentrated. Purification by flash chromatography (methanol/methylene chloride, 1:9) afforded the coupled amide compound (0.22 g, 28%). ESI mass spectrum analysis m/z (relative intensity): 500 (M⁺, 100). Reduction of the benzonitrile to the benzylamine followed by standard HPLC purification protocols via methods previously described afforded pure titled compound as colorless crystals. ¹ HNMR (CD₃ OD)δ: 8.61 (bs, 1H), 8.14 (bs, 1H), 8.09 (dd, J=7.7 Hz, 1H), 7.65-7.50 (m, 12H), 7.40 (dd, J=8.8 Hz, 2H), 7.32 (dd, j=7.3 Hz, 1H), 4.91 (s, 3H) ppm. ESI mass spectrum analysis m/z (relative intensity): 448.2 (M+H, 100).

EXAMPLE 192 1-(3-aminomethylphenyl)-5-[(2'-methylsulfonylmethyl-[1,1']-biphen-4-yl)aminocarbonyl]imidazole, Trifluoroacetic Acid Salt

The title compound was prepared in a similar manner to Example 197. ¹ HNMR (CD₃ OD)δ: 8.57 (s, 1H), 8.15 (m, 2H), 7.72-7.58 (m, 12H), 7.40 (m, 3H), 4.22 (s, 2H0, 2.72 (s, 3H) ppm. ESI mass spectrum analysis m/z (relative intensity): 447 (M+H, 100).

EXAMPLE 193 1-(3-amidinophenyl)-5-[(2'-aminosulfonyl[1,1']-biphen-4-yl)aminocarbonyl]imidazole, Trifluoroacetic Acid Salt

The benzonitrile obtained in part C in Example 197 was subjected to the Pinner-amidine reaction protocol and further purified via methods described previously to obtain the title compound as colorless crystals. ESI mass spectrum analysis m/z (relative intensity): ¹ HNMR (CD₃ OD)δ: 8.76 (s, 1H), 8.21 (s, 1H), 8.07 (d, J=7.7 Hz, 1H), 7.98 (d, J=8.4 Hz, 1H), 7.89 (d, J=8.4 Hz, 1H0, 7.79 (t, J=7.7 Hz, 1H), 7.59 (m, 3H), 7.50 (t, J=7.7 Hz, 1H), 7.38 (d, J=8.5 Hz, 2H), 7.30 (d, J=8.7 Hz, 1H) ppm. ESI mass spectrum analysis m/z (relative intensity) 461.2 (M+H, 100).

EXAMPLE 194 1-[3-(methylaminomethyl)phenyl]-5-[(2'-aminosulfonyl-3-fluoro-[1,1']-biphen-4-yl)aminocarbonyl]-3-methylpyrazole, Trifluoroacetic Acid Salt

Part A. Preparation of ethyl 1-[3-(N-t-butoxycarbonyl-aminomethyl)phenyl]-3-methylpyrazolecarboxylate

To a solution of 1.52 g (5.14 mmol) of ethyl 1-[3-(aminomethyl)phenyl]-3-methylpyrazolecarboxylate hydrochloride in 10 mL of THF under N₂ was added 1.49 g (14.7 mmol) of triethylamine and 1.35 g (6.17 mmol) di-t-butyl dicarbonate. The mixture was allowed to stir at room temperature for 16 hours. Water (25 mL) was added and the mixture was extracted with 25 mL ether three times. The combined organic extracts were dried over MgSO₄ and the solvent evaporated to give the desired product (1.85 g, 74%) as a white solid. ¹ HNMR (CDCl₃)δ: 7.34 (m, 4H); 6.81 (s, 1H); 4.87 (b s, 1H); 4.37 (d, J=7, 2H); 4.22 (q, J=7, 2H); 2.35 (s, 3H); 1.45 (t, 9H); 1.24 (t, J=7, 3H).

Part B. Preparation of ethyl 1-[3-(N-t-butoxycarbonyl-N-methylaminomethyl)phenyl]-3-methylpyrazolecarboxylate

To a solution of 1.85 g (5.15 mmol) of ethyl 1-[3-(N-t-butoxycarbonylaminomethyl)phenyl]-3-methylpyrazolecarboxylate in 10 mL of THF under N₂ was added 0.15 g (5.88 mmol) of 95% sodium hydride. After 1 hour, the gas evolution ceased and 0.83 g (5.88 mmol) of methyl iodide was added. The mixture was allowed to stir at room temperature for 16 hours. Water (25 mL) was added and the mixture was extracted with 25 mL ether three times. The combined organic extracts were dried over MgSO₄ and the solvent evaporated and then chromatographed with 20% EtOAc/hexanes on silica to give the desired product (0.52 g, 27%) as a white solid. An additional 0.83 g of non-methylated starting material was also isolated. ¹ HNMR (CDCl₃)δ: 7.40 (m, 1H); 7.30 (m, 3H); 6.81 (s, 1H); 4.47 (b s, 2H); 4.22 (q, J=7, 2H); 2.83 (b m, 3H); 2.34 (s, 3H); 1.47 (b s, 9H); 1.23 (t, J=7, 3H).

Part C. Preparation of 1-[3-(N-t-butoxycarbonyl-N-methylaminomethyl)phenyl]-3-methylpyrazolecarboxylic Acid

To a solution of 0.52 g (1.39 mmol) of ethyl 1-[3-(N-t-butoxycarbonyl-N-methylaminomethyl)phenyl]-3-methylpyrazole-carboxylate in 5 mL of THF was added 1.4 mL (1.4 mmol) of 1M aqueous lithium hydroxide. The mixture was allowed to stir at room temperature for 6 hours. Water (10 mL) was added and the mixture was extracted with 25 mL ether twice. The aqueous layer was acidified with 1N HCl to pH 4 and extracted with 25 mL ether three times. The combined organic layers from the second set of extractions were dried over MgSO₄ and the solvent evaporated to give the desired product (0.35 g, 74%) as a white solid. ¹ HNMR (CDCl₃)δ: 7.38 (m, 4H); 6.87 (s, 1H); 4.46 (b s, 2H); 2.83 (b m, 3H), 2.37 (s, 3H), 1.46 (b s, 9H).

Part D. Preparation of 1-[3-(methylaminomethyl)phenyl]-5-[(2'-aminosulfonyl-3-fluoro-[1,1']-biphen-4-yl)aminocarbonyl]-3-(methyl)pyrazolecarboxamide, Trifluoroacetic Acid Salt

To a solution of 1-[3-(N-t-butoxycarbonyl-N-methylaminomethyl)phenyl]-3-methylpyrazolecarboxylic acid (0.176 g, 0.509 mmol) in 10 mL of CH₂ Cl₂ was added 10 μL of DMF and oxalyl chloride (97 mg, 0.763 mmol). The solution was allowed to stir for 1.5 hours under Ar and then solvent was evaporated under high vacuum. The resulting solid was redissolved in 10 mL and triethylamine (0.15 g, 1.53 mmol) and 2'-(t-butylaminosulfonyl)-3-fluoro-[1,1']-biphenyl (0.172 g, 0.534 mmol) were added. After stirring for 16 hours under Ar, the reaction mixture was added to water and extracted with ethyl acetate. The solvent was evaporated and the mixture was dissolved in 5 mL of TFA. This solution was heated to 50° C. for 4 hours, cooled to room temperature and the solvent evaporated. The crude benzylamine was purified by HPLC (C18 reversed phase) eluting with 0.5% TFA in H₂ O/CH₃ CN to give 60 mg (19%) of the desired salt. ¹ HNMR (DMSO-d₆)δ: 8.75 (br s, 2H); 8.00 (m, 1H), 7.63-7.15 (m, 1OH); 6.94 (s, 1H); 4.15 (b t, J=6, 2H); 2.54 (t, J=5, 2H); 2.45 (s, 3H). ESI mass spectrum analysis m/z (relative intensity): 494.1 (M+H, 100).

EXAMPLE 195 1-[3-(methylaminomethyl)phenyl]-5-[(2'-methylsulfonyl-3-fluoro-[1,1']-biphen-4-yl) aminocarbonyl]-3-methylpyrazole, Trifluoroacetic Acid Salt

To a solution of 1-[3-(N-t-butoxycarbonyl-N-methylaminomethyl)phenyl]-3-methylpyrazolecarboxylic acid (0.176 g, 0.509 mmol) in 10 mL of CH₂ Cl₂ was added 10 μL of DMF and oxalyl chloride (97 mg, 0.763 mmol). The solution was allowed to stir for 1.5 hours under Ar and then solvent was evaporated under high vacuum. The resulting solid was redissolved in 10 mL and triethylamine (0.15 g, 1.53 mmol) and 2'-(methylsulfonyl)-3-fluoro-[1,1']-biphenyl (0.172 g, 0.534 mmol) were added. After stirring for 16 hours under Ar, the reaction mixture was added to water and extracted with ethyl acetate. The solvent was evaporated and the mixture was dissolved in 5 mL of TFA. This solution was heated to 50° C. for 4 hours, cooled to room temperature and the solvent evaporated. The crude benzylamine was purified by HPLC (C18 reversed phase) eluting with 0.5% TFA in H₂ O/CH₃ CN to give 140 mg (45%) of the desired salt. ¹ HNMR (DMSO-d₆)δ: 8.76 (br s, 2H); 8.06 (dd, J=8, 1, 1H); 7.77-7.61 (m, 4H); 7.52-7.31 (m, 5H); 7.19 (dd, J=8, 1.5, 1H); 6.95 (s, 1H); 4.17 (b t, J=6, 2H); 2.90 (s, 3H); 2.54 (t, J=5, 2H); 2.29 (s, 3H). ESI mass spectrum analysis m/z (relative intensity): 492.2 (M+H).

EXAMPLE 196 1-(3-aminomethylphenyl)-5-[(2'-methylsulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-4-methoxy-3-trifluoromethyl Pyrazole, Trifluoroacetic Acid Salt

Part A. To 1-(3-cyanophenyl)-4-methoxy-3-trifluoromethylpyrazole carboxylic acid (0.69 g, 2.2 mmol) was added CH₂ Cl₂ (15 mL), oxalyl chloride (0.27 mL, 3.1 mmol), and three drops of DMF. The reaction was stirred for 2h. The solvents were removed and fresh CH₂ Cl₂ (15 mL), 4-bromo-aniline (0.38 g, 2.2 mmol) and DMAP (0.68 g,5.5 mmol) were added and the reaction was stirred 18h. Dilution with CH₂ Cl₂, followed by washing successively with 1N HCl, saturated NaHCO₃, brine, drying (MgSO₄) and recrystallization with CH₂ Cl₂ /hexanes afforded 0.5 g (48%) pure product and 0.43 g from filtrate. ¹ HNMR (CDCl₃) δ: 8.90 (s,1H), 7.79 (m,2H), 7.72 (dd, J=1.83, 6.96 Hz, 1H), 7.63 (t, J=8.06 Hz, 1H), 7.46 (s,4H), 4.15 (s, 3H) ppm; ESI mass spectrum analysis m/z (relative intensity): 482-484 (M+H, 100).

Part B To the bromo compound (0.4 g, 0.86 mmol) from Part A was added 2-thiomethyl phenylboronic acid (0.18 g, 1.1 mmol), 2M Na₂ CO₃ (1 mL), toluene (15 mL), and ethanol (15 mL). The mixture was degassed and tetrakistriphenylphosphine palladium (0) (40 mg) was added and the reaction was heated to reflux 18h. The reaction was cooled, filtered, concentrated, and extracted with ethyl acetate and dried (MgSO₄). The compound was purified by chromatography on silica gel eluting with (4:1) hexanes/ethyl acetate to afford 0.195 g (46%) yellow solid. ¹ HNMR (CDCl₃)δ: 8.95 (s,1H), 7.80 (m,3H), 7.63 (d, J=8.42 Hz, 2H), 7.61 (m,1H), 7.44 (d, J=8.43 Hz, 2H), 7.34 (m,2H), 7.20 (m,2H), 4.15 (s,3H), 2.37 (s,3H) ppm.

Part C To the product (0.19 g,0.37 mmol) of Part B in CH₂ Cl₂ (15 mL), cooled to 0° C., m-chloroperbenzoic acid (0.33 g, 1.1 mmol) was added. The reaction warmed to ambient temperature overnight. The reaction was washed with water, sodium bisulfite solution, NaHCO₃ and dried (MgSO₄). The compound was purified by chromatography on silica gel eluting with (1:1) hexanes/ethyl acetate to afford 0.192 g (95%) yellow solid. ¹ HNMR (CDCl₃)δ: 9.02 (s,1H), 8.24 (dd, J=1.46, 7.69 Hz, 1H), 7.80 (m,3H), 7.66 (d, J=8.06 Hz, 2H), 7.65 (m,3H), 7.49 (d, J=8.79 Hz, 2H), 7.37 (dd, J=1.46, 7.69 Hz, 1H), 4.18 (s,3H), 2.68 (s,3H); ESI mass spectrum analysis m/z (relative intensity): 563 (M+Na, 100).

Part D The product of Part C was hydrogenated in EtOH/TFA with 10% palladium on carbon catalyst at 50 psi for 24h. Purification by reverse phase HPLC and freeze-drying afforded the title compound 0.16 g(69.6%), ¹ HNMR (DMSO-d₆)δ: 11.11 (s,1H), 8.25 (brd s,2H), 8.10 (d, J=8.06 Hz, 1H), 7.77 (s+d,J=8.79 Hz, 2H), 7.69 (s+d, J=7.32 Hz, 3H), 7.60 (s+m,3H), 7.41 (m,3H), 4.15 (brd s,2H), 3.95 (s,3H) 2.88 (s,3H) ppm; HRMS 545.147037 (calc'd), 545.146284 (obs.); Elemental analysis calc'd for C₂₆ H₂₃ F₃ N₄ O₄ S (TFA) (H₂ O)1.3: C:49.31,H:3.93,N:8.22, found C:49.46,H:3.62,N:8.09.

EXAMPLE 197 1-(3-aminomethylphenyl)-5-[(2-fluoro-4-(N-pyrrolidinocarbonyl)phenyl)aminocarbonyl]-3-trifluoromethylpyrazole, Trifluoroacetic Acid Salt

Part A. To 1-(3-cyanophenyl)-3-trifluoromethylpyrazole carboxylic acid (0.29 g,1.0 mmol) in CH₂ Cl₂ (40 mL) was added oxalyl chloride (0.135 mL, 1.6 mmol) and several drops DMF. The reaction was stirred for 2h, then concentrated. To the acid chloride was added fresh CH₂ Cl₂ (40 mL), 2-fluoro-4-(N-pyrrolidinocarbonyl)aniline (0.22 g, 1 mmol), and DMAP (0.32 g, 2.6 mmol) and the reaction was stirred 18h. The reaction was washed successively with 1N HCl, NaHCO₃, and dried (MgSO₄). The compound was purified by chromatography on silica gel eluting with (1:1.5) hexanes/ethyl acetate to afford 0.345 g (71%). ¹ HNMR (CDCl₃) δ: 9.03 (s,1H), 7.86 (m,4H), 7.63 (t,J=8.05 Hz, 1H), 7.55 (s,1H), 7.21 (m,2H), 3.67 (t, J=8.05 Hz, 2H), 3.43 (t, J=6.59 Hz, 2H), 2.02 (q, J=6.22 Hz, 2H), 1.92 (q, J=6.22 Hz, 2H) ppm; ESI mass spectrum analysis m/z (relative intensity): 472.1 (M+H)⁺, 494 (M+Na)⁺.

Part B. The product of Part A was hydrogenated in EtOH/TFA with 10% palladium on carbon catalyst at 50 psi for 24h. Purification by reverse phase HPLC and freeze-drying afforded 0.34 g (80%) product. ¹ HNMR (DMSO-d₆)δ: 10.8 (s,1H), 8.23 (s,2H), 7.72 (m+d,J=8.06 Hz, 3H), 7.59 (m,3H), 7.49 (dd,J=1.84, 11.36 Hz, 1H), 7.39 (dd, J=8.06, 1.83 Hz, 1H), 4.15 (q, J=5.86 Hz, 2H), 3.47 (t, J=6.6 Hz, 2H), 3.42 (t,J=6.2 Hz, 2H), 1.89 (m,4H) ppm; ESI mass spectrum analysis m/z: 476.2 (M+H)⁺ ; Elemental analysis calc'd for C₂₃ H₂₁ F₄ N₅ O₂ (TFA) (H₂ O)0.5: C:50.17,H:3.87,N:11.70, found C:50.05,H:3.87,N:11.43

EXAMPLE 198 1-(3-aminomethylphenyl)-5-[(3-fluoro-4-(N-pyrrolidinocarbonyl) phenyl)aminocarbonyl]-3-trifluoromethylpyrazole, Trifluoroacetic Acid Salt

Part A. 1-(3-Cyanophenyl)-3-trifluoromethylpyrazole carboxylic acid and 3-fluoro-4-(N-carbonylpyrrolidino)aniline were coupled via the acid chloride as in the previous Example in 81% yield. ¹ HNMR (CDCl₃) δ 10.01 (s,1H), 7.79 (m,4H), 7.61 (t, J=7.69 Hz, 1H), 7.16 (dd,J=1.84, 10.99 Hz, 1H), 7.06 (t, J=8.06 Hz, 1H), 6.93 (dd, J=1.83, 8.05 Hz, 1H), 3.68 (t, J=6.59 Hz, 2H), 3.34 (t, J=6.59 Hz, 2H), 2.00 (q, J=6.59 Hz, 2H), 1.94 (q, J=6.59 Hz, 2H) ppm; ESI mass spectrum analysis m/z (relative intensity): 472.1 (M+H)⁺, 494 (M+Na)⁺.

Part B. The product of Part A was hydrogenated in EtOH/TFA with 10% palladium on carbon catalyst at 50 psi for 24h. Purification by reverse phase HPLC and freeze-drying afforded 0.38 g (84%) product. ¹ HNMR (DMSO-d₆)δ: 11.07 (s,1H), 8.24 (s,2H), 7.73 (m,3H), 7.63 (m,3H), 7.50 (m,2H), 4.16 (d, j=5.49 Hz, 2H), 3.47 (t, J=6.23 Hz, 2H), 3.23 (t,J=6.23 Hz, 2H), 1.89 (m,4H) ppm; HRMS 476.170963 (calc'd), 476.171044 (obs.); Elemental Analysis calc'd for C₂₃ H₂₁ F₄ N₅ O₂ (TFA) (H₂ O)0.5: C:50.17,H:3.87,N:11.70, found C:50.17,H:3.85,N:11.48.

EXAMPLE 199 1-(3-aminomethylphenyl)-5-[(2'-sulfonylmethyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-trifluoromethyl-pyrazole, Trifluoroacetic Acid Salt

1-(3-Cyanophenyl)-5-[(2'-sulfonylmethyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-trifluoromethyl-pyrazole (synthesis previously described) was hydrogenated in EtOH/TFA with 10% palladium on carbon catalyst at 50 psi for 24h. Purification by reverse phase HPLC and freeze-drying afforded the title compound. ¹ HNMR (DMSO-d₆)δ: 10.92 (s,1H), 8.24 (bd s,2H),8.10 (d, J=7.69 Hz, 1H), 7.79 (m,6H), 7.60 (m,3H), 7.41 (s+d, J=8.79 Hz, 3H), 4.17 (q, J=5.12 Hz, 2H), 2.85 (s,3H) ppm, HRMS 515.136472 (calc'd), 515.137193 (obs).

EXAMPLE 200 1-(3-aminomethylphenyl)-5-[(2'-aminosulfonyl-3-fluoro-[1,1']biphen-4-yl)aminocarbonyl]-3-trifluoromethyl-pyrazole, Trifluoroacetic Acid Salt

Part A. 1-(3-Cyanophenyl)-3-trifluoromethylpyrazole carboxylic acid and 1-(2'-tertbutylaminosulfonyl-[1,1']-3-fluorobiphenylaniline were coupled via the acid chloride as in previous Examples in 76% yield. ¹ HNMR (CDCl₃) δ: 8.31 (t, J=8.43 Hz, 1H), 8.18 (dd,J=1.47, 7.69 Hz, 1H), 8.04 (s,1H), 7.88 (d, J=1.46 Hz, 1H), 7.83 (m,2H), 7.68 (d, J=8.06 Hz, 1H), 7.62 (m,2H), 7.42 (dd, J=1.83, 11.72 Hz, 1H), 7.29 (d, J=1.47 Hz, 1H), 7.22 (m,2H),3.69 (s,1H),1.07 (s,9H) ppm; ESI mass spectrum analysis m/z (relative intensity): 607.9. (M+Na, 100).

Part B. The product of Part A was refluxed in TFA for 30 minutes then hydrogenated in EtOH/TFA with 10% palladium on carbon catalyst at 50 psi for 24h and then with platinum (II) oxide catalyst at 50 psi for 24h. Purification by reverse phase HPLC and freeze-drying afforded 0.16 g (44%) product. ¹ HNMR (DMSO-d₆) δ: 10.71 (s,1H), 8.24 (bd s,2H), 8.05 (dd, J=1.47, 6.96 Hz, 1H), 7.74 (s,1H), 7.69 (s,1H), 7.66 (m,6H),7.43 (s,2H), 7.35 (m,2H), 7.23 (d, J=8.42 Hz, 1H), 4.16 (q, J=5.49 Hz, 2H) ppm; ESMS 534.1 (M+H); Elemental Analysis calc'd for C₂₄ H₁₉ F₄ N₅ O₃ S (TFA) 1.1 (H₂ O) 0.6: C:46.99,H:3.21,N:10.46, found C:47.06,H:2.86,N:10.37.

EXAMPLES 201 AND 202 1-(3-aminomethylphenyl)-5-[(5-(2'-aminosulfonylphenyl)-[1,6-dihydro]pyrimid-2-yl)aminocarbonyl]-3-trifluoromethyl-pyrazole, Trifluoroacetic Acid Salt and 1-(3-aminomethylphenyl)-5-[(5-(2'-aminosulfonylphenyl)pyrimid-2 -yl) aminocarbonyl]-3-trifluoromethyl-pyrazole, Trifluoroacetic Acid Salt

1-(3-Cyanophenyl)-5-[(5-(2'-tertbutylaminosulfonylphenyl-4-yl)pyrimid-2-yl)aminocarbonyl]-3-trifluoro-methyl pyrazole (0.3 g, 0.5 mmol) (synthesis previously described) was hydrogenated in ethanol/acetic acid for 24h at 40 psi, first with 10% palladium on carbon and then with added platinum (II) oxide. The reaction was filtered, concentrated, and refluxed in TFA for 30 minutes. Purification by reverse phase HPLC and freeze-drying afforded small amounts of two products. The dihydro-compound was the first product obtained (64.5 mg). ¹ HNMR (DMSO-d₆)δ: 9.76 (s,1H), 9.10 (s,1H), 8.22 (brd,2H), 7.95 (dd,J=1.10, 7.69 Hz, 1H), 7.65 (s,1H), 7.61 (m,5H), 7.49 (s,2H), 7.41 (dd, J=1.46, 7.32 Hz, 1H), 7.19 (s,1H), 6.10 (d, J=4.40 Hz, 1H), 4.22 (s,2H), 4.15 (q, J=5.86 Hz, 2H) ppm; HRMS 520.137869 (calc'd); 520.138256 (obs); Elemental Analysis calc'd for C₂₂ H₂₀ F₃ N₇ O₃ S (TFA) 2: C:41.77,H:2.97,N:13.12, found C:41.98,H:3.02,N:12.97. The second product was the pyrimidyl analog. ¹ HNMR (DMSO-d₆) δ: 11.61 (s,1H), 8.66 (s,2H),8.24 (brd,2H), 8.08 (dd,J=2.20, 6.95 Hz, 1H), 7.73 (m,4H), 7.60 (m,5H), 7.48 (m,1H), 4.16 (m,2H); HRMS 518.122219 (calc'd); 518.122803 (obs); Elemental Analysis calc'd for C₂₂ H₁₈ F₃ N₇ O₃ S (TFA) 1.3 (H₂ O) C:43.79,H:3.03,N:14.53, found C:43.92,H:2.99,N:14.37.

EXAMPLE 203 1-[3-(2'-ethylaminophenyl)-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-trifluoromethyl pyrazole, Trifluoroacetic Acid Salt

Part A. To 1-(3-cyanophenyl)-5-hydroxymethyl-3-trifluoromethyl pyrazole (1.8 g, 6.7 mmol) in DMF (12 mL) was added tert-butyldimethylsilylchloride (1 g, 7.1 mmol) and imidazole (0.94 g, 13.8 mmol). The reaction was stirred for 3h, then partitioned between ethyl acetate and water. Extraction with ethyl acetate, drying (MgSO₄) and purification by chromatography on silica gel eluting with (4:1) hexanes/ethyl acetate to afford 1.88 g (73%).

Part B. To the product of Part A (0.4 g, 1.0 mmol) in THF (15 mL) at 0° C. was added methyl magnesium chloride (0.9 mL, 2.6 mmol) and the reaction was stirred at ambient temperature for 2h. After cooling to 0° C., methanol (25 mL) and then sodium borohydride (0.2 g, 5 mmol) were added and the reaction was stirred for 1h. The reaction was quenched with water, filtered and concentrated. The residue was extracted into ethyl acetate and dried (MgSO₄). The crude oil was dissolved in CH₂ Cl₂, cooled to 0° C. and ditert-butylcarbamate (0.23 g, 1.1 mmol) and triethylamine(0.15 mL) were added. The reaction was stirred 18h, then washed with saturated ammonium chloride, brine and dried (MgSO₄). The crude material was dissolved in THF and tetrabutylammonium fluoride in THF (1.46 mL) was added. The reaction stirred for 3h, then concentrated. The residue was dissolved in CH₂ Cl₂, and washed with water, brine and dried (MgSO₄). Purification by chromatography on silica gel eluting with (2:1) hexanes/ethyl acetate afforded 0.187 g (47%). ¹ HNMR (CDCl₃) δ7.58 (s,1H), 7.47 (m,2H), 7.38 (m,1H), 6.70 (s,1H), 4.92 (bd,1H), 4.78 (m,1H), 4.65 (m,2H), 2.9i (bd,1H), 1.49 (d, J=6.96 Hz, 3H), 1.40 (s,9H) ppm; MS ESI mass spectrum analysis m/z (relative intensity): 407.8 (M+Na, 100).

Part C. To the product of Part B (0.17 g, 0.44 mmol) in acetonitrile (5 mL) at 0° C. was added a few crystals of ruthenium (III) chloride and aqueous solution of sodium periodinate (0.2 g, 0.9 mmol). The reaction was stirred 18h, then filtered and concentrated. The aqueous residue was extracted with ethyl acetate and dried (MgSO₄). ESI (-ve) mass spectrum analysis m/z (relative intensity): 398 (M-H, 100).

Part D. To the product of Part C (0.17 g,0.4 mmol) and 4-bromoaniline (0.073 g,0.4 mmol) in CH₂ Cl₂ (5 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.11 g, 0.57 mmol). The reaction was stirred 18h, then washed with water, brine and dried (MgSO₄). Filtration through a plug of silica gel eluting with (1:1) hexanes/ethyl acetate afforded 0.148 g of a white foam. ESI mass spectrum analysis m/z (relative intensity): 575-577 (M+Na)⁺.

Part E. The product of Part D (0.14 g, 0.26 mmol) was coupled to 2-tert-butylsulfonamide phenyl boronic acid by standard Suzuki procedure. The crude product of this reaction was heated to reflux in TFA for 20 minutes. Purification by reverse phase HPLC and freeze-drying afforded 77 mg product (46%). ¹ HNMR (DMSO-d₆)δ: 10.86 (s,1H), 8.32 (brd,2H), 8.04 (dd,j=7.69, 1.42 Hz, 1H), 7.76 (s,1H), 7.68 (d,j=8.42 Hz, 2H), 7.67 (m,6H), 7.39 (d, J=8.79 Hz, 2H), 7.32 (dd, J=9, 1.32 Hz, 1H), 7.29 (s,2H), 4.56 (m,1H), 1.52 (d,J=6.96 Hz, 3H) ppm; HRMS 530.147371 (cal'd), 530.148939 (obs); Elemental Analysis calc'd for C₂₅ H₂₂ F₃ N₅ O₃ S (TFA) 1.1: C:49.88,H:3.55,N:10.69, found C:49.49,H:3.49,N:10.60.

EXAMPLE 204 1-[3-(1-(N-morpholino)imino)phenyl]-5-[(2'-aminosulfonyl-3-fluoro-[1,1']-biphen-4-yl)aminocarbonyl]-3-trifluoromethylpyrazole, Trifluoroacetic Acid Salt

To 1-(3-cyanophenyl)-5-[(2'-tert-butylaminosulfonyl-3-fluoro-[1,1']-biphen-4-yl)aminocarbonyl]-3-trifluoromethyl pyrazole (0.23 g, 0.39 mmol) in (2:1) CHCl₃ /MeOH (30 mL) at 0° C. was bubbled HCl gas for 15 minutes. The flask was sealed and placed in the refrigerator for 18h. The solvent was removed and morpholine (0.2 mL) and fresh methanol were added. The reaction was stoppered and stirred for 48h. The solvent was removed and the residue was heated to reflux in TFA for 15 minutes. Purification by reverse phase HPLC and freeze-drying afforded 0.146 g product (51%). ¹ HNMR (DMSO-d₆)δ: 10.70 (s,1H), 9.69 (s,1H), 9.32 (s,1H), 8.05 (dd, j=6.96, 2.20 Hz, 1H), 7.94 (s,1H), 7.89 (d,J=8.05 Hz, 1H), 7.80 (m,2H), 7.65 (m,3H), 7.42 (s,2H), 7.35 (d, J=8.50 Hz, 2H), 7.23 (d, J=9.52 Hz, 1H), 3.81 (bs, 2H), 3.74 (bd s,2H), 3.56 (bd s,2H), 3.32 (bd s,2H) ppm; SMS 616.9 (M+H). Elemental Analysis calc'd for C₂₈ H₂₄ F₄ N₆ O₄ S (TFA) 1.1 (H₂ O) 1.2: C:47.50,H:3.63, N:11.01, found C:47.39,H:3.28,N:10.69.

EXAMPLE 205 1-(3-aminomethylphenyl)-5-[2-(2'-aminosulfonyl-[1,1']-biphen-4-yl)-1-hydroxyethyl]-3-trifluoromethyl-pyrazole, Trifluoroacetic Acid Salt

Part A. To 1-(3-cyanophenyl)-3-trifluoromethylpyrazole-5-carboxylic acid (1 g, 3.6 mmol) in CH₂ Cl₂ (40 mL) was added oxalyl chloride (0.4 mL, 4.9 mmol) and several drops of DMF. The reaction was stirred for 3h, then the solvent was removed in vacuo. In a separate flask, dibromoethane (0.1 mL), was added to activated Zn (0.35 g, 5.3 mmol) in THF (5 mL). The mixture was heated to reflux for 5 minutes, then cooled to 0° C. and 4-bromo-benzylbromide (1.1 g, 4.3 mmol) in THF (5 mL) was added slowly over 0.5h. The reaction was kept at 0° C. for 3h, then cannulated into a mixture of CuCN (0.38 g ,4.3 mmol), LiCl (0.36 g, 8.5 mmol) and THF (10 mL) at -78° C. The reaction was warmed to -20° C. for 5 minutes, then recooled to -78° C. The solid acid chloride was suspended in THF (20 mL) and added to the above cold mixture. The reaction was allowed to slowly warm to room temperature, then, filtered and concentrated. Purification by chromatography on silica gel eluting with (2:1) hexanes/ethyl acetate afforded 0.55 g (37%) white foam. MS (ESI) m/z=433.9-432 (M-H)⁺.

Part B. The product of Part A (0.53 g, 1.2 mmol) was coupled by standard Suzuki procedures to 2-tert-butylaminosulfonylphenyl boronic acid (0.39 g, 1.7 mmol). Purification by chromatography on silica gel eluting with (4:1) hexanes/ethyl acetate afforded 0.32 g (46%) the keto-nitrile coupled product. MS (ESI) m/z=565 (M-H)⁺.

Part C. To the product from Part B (0.05 g, 0.08 mmol) was added CH₂ Cl₂ (10 mL) and tetra-N-butylammonium borohydride (0.08 g, 0.31 mmol) and the mixture was heated to reflux 18h. The solvent was removed and replaced with 10% HCl and heated to reflux for 1h. The reaction was cooled, extracted with diethyl ether, basefied with 50% NaOH, extracted with ethyl acetate and dried (MgSO₄). The diethyl ether layer contained tert-butyl protected intermediate. The ether was concentrated and the residue heated in TFA for 15 minutes. All product was combined and purification by reverse phase HPLC and freeze-drying afforded 0.01 g of product (18%). ¹ HNMR (DMSO-d₆)δ: 8.23 (brd, 2H), 8.03 (d, j=6.96 Hz, 1H), 7.63 (m, 6H), 7.28 (s+d, j=7.69 Hz, 3H), 7.18 (s, 2H), 7.11 (s+d, j=6.59 Hz, 3H), 5.83 (m, 1H), 4.81 (m, 1H), 4.15 (m, 2H), 3.09 (d, j=6.60 Hz, 2H) ppm; HRMS 517.152122(calc'd), 517.152222(obs.).

EXAMPLE 206 1-(3-aminomethylphenyl)-5-[(3-fluoro-2'-methylsulfonyl-1,1']-biphen-4-yl)aminocarbonyl]-3-trifluoromethyl Pyrazole, Trifluoroacetic Acid Salt

Part A. To 1-(3-cyanophenyl)-3-trifluoromethylpyrazole-5-carboxylic acid (1 g, 3.6 mmol) in CH₂ Cl₂ (40 mL) was added oxalyl chloride (0.43 mL, 4.9 mmol) and several drops of DMF. The reaction was stirred 18h, then the solvent was removed in vacuo. Fresh CH₂ Cl₂ (40 mL) was added followed by 4-bromo-2-fluoroaniline (0.68 g, 3.6 mmol) and 4-dimethylaminopyridine (1.09 g, 8.9 mmol). After stirring 18h, the reaction was washed with 1N HCl, sat'd NaHCO₃, dried (Na₂ SO₄), filtered and concentrated to afford 1.55 g crude bromide. ESI (-ve) mass spectrum analysis m/z (relative intensity) 450.8-452.8 (M-H, 100).

Part B. The bromide from Part A (0.5 g, 1.1 mmol), 2-thiomethyl phenylboronic acid (0.26 g, 1.5 mmol), and 2M Na₂ CO₃ (2 mL), were combined in (1:1) ethanol/toluene (20 mL) and degassed by bubbling nitrogen through for 30 minutes. Tetrakis-triphenylphosphine palladium(0) (50 mg) was added and the reaction heated to reflux 18h. The reaction was cooled, concentrated, extracted with ethyl acetate and dried (MgSO₄). The coupled product was purified through a plug of silica gel using (1:1) hexane/ethyl acetate as eluent and carried onto the next step. The thiomethyl compound was dissolved in CH₂ Cl₂ (50 mL), cooled to 0° C., and MCPBA (0.67 g, 2.2 mmol) was added. The reaction was stirred 48 h, then washed successively with aqueous sodium bisulfite, brine, and dried (MgSO₄). The sulfone was purified through a plug of silica gel using (1:1) hexane/ethyl acetate as eluent to afford 0.34 g. ¹ HNMR(CDCl₃) δ: 8.25 (t, 1 H), 7.90-7.15 (m, 12 H), 2.39 (s, 3 H) ppm. ESI mass spectrum analysis m/z 550.7 (M+Na)+, 526.7 (M-H)+.

Part C The product of Part B (0.34 g, 0.6 mmol) was hydrogenated in (1:2)methanol/ethanol (70 mL) and TFA (1 mL) with 10% palladium on carbon catalyst at 50 psi for 24 h. Purification by reverse phase HPLC and freeze-drying afforded 0.21 g (50%) product. 1HNMR(DMSO-d₆) δ: 10.75 (s, 1 H), 8.23 (m, 3 H), 8.11 (dd, j=7.69, 1.46 Hz, 1 H), 7.96 (dd, j=6.96, 1.47 Hz, 1 H), 7.81 (m, 8 H), 7.26 (dd, j=1.47, 8.06 Hz, 1 H), 4.16 (q, j=5.49 Hz, 2 H), 2.94 (s, 3 H) ppm; ESI mass pectrum analysis m/z 532.9 (M+H, 100); Elemental Analysis calc'd for C₂₅ H₂₀ F₄ N₄ O₃ S(TFA)1.1: C.:49.65, H:3.23,N:8.52, found C:49.73,H:2.98,N:8.40.

EXAMPLE 207 1-(3-aminomethylphenyl)-5-[(5-(2,1-methylsulfonyl-phenyl) pyrimid-2-yl)aminocarbonyl]-3-trifluoromethyl pyrazole,trifluoroacetic acid salt.

Part A. 1-(3-Cyanophenyl)-3-trifluoromethylpyrazole carboxylic-5-acid (2.2,7.8 mmol) was heated to reflux in methanol containing con. sulfuric acid (1 mL) for 48 h. The solvent was removed and the residue was dissolved in ethyl acetate, washed with NaHCO₃ (sat.), brine and dried (MgSO₄). The ester was hydrogenated in MeOH/TFA with 10% palladium on carbon catalyst at 40 psi for 24 h. The reaction was filtered and concentrated. The residue was suspended in CH₂ Cl₂, cooled to 0° C. and lN NaOH (35 mL) and benzyl chloroformate (1.2 mL, 8.6 mmol) were added. The reaction was stirred 2 h then separated and the organics dried (MgSO₄) and concentrated. The residue was dissolved in MeOH, cooled to 0° C. and a solution of

LiOH (0.5 g,11.8 mmol) in water was added. The reaction was stirred 18 h. The reaction was concentrated and the residue was acidified and extracted with ethyl acetate and dried (MgSO₄) to afford 1.83 g (57%) white solid. ESI mass spectrum analysis m/z (relative intensity): 417.9 (M-H, 100).

Part B. The acid from Part A (0.46 g, 1.1 mmol) was coupled with 2-amino-5-(2'-methylsulfonylphenyl)pyrimidine (0.31 g,1.1 mmol) by the standard acid chloride procedure to afford 0.3 g (42%) of the carbobenzyloxy protected intermediate. The intermediate was heated to reflux in TFA for 45 minutes and purification by reverse phase HPLC and freeze-drying afforded 0.16 g (23% overall)product. ¹ HNMR(DMSO-d₆) δ: 11.65 (s, 1 H), 8.72 (s, 2 H), 8.24 (bd, 2 H), 8.15 (d, J=7.69 Hz, 1 H), 7.87 (m, 4 H), 7.58 (s+m, 3 H), 7.54 (d, J=7.32 Hz, 1 H), 4.16 (q, J=5.49 Hz,2 H), 3.07 (s, 3 H) ppm; HRMS 517.126970 (calc'd), 517.125600 (obs); Elemental Analysis calc'd for C₂₃ H₁₉ F₃ N₆ O₃ S (TFA) 1.2: C:46.70,H:3.12,N:12.86, found C:46.78,H:3.04,N:12.56.

EXAMPLE 208 1-[3-amidinophenyl]-5-[(3-fluoro-2'-methylsulfonyl-[1,1']-biphen-4-yl) aminocarbonyl]3-trifluoromethyl pyrazole, trifluoroacetic acid salt

The nitrile prepared as in Example 206 was subjected to standard Pinner reaction conditions and purification by reverse phase HPLC and freeze-drying afforded 0.067 g (27%) of the desired titled product. ¹ HNMR(DMSO-d₆) δ: 10.74 (s, 1 H), 9.45 (s, 1.5 H), 9.13 (s, 1.5 H), 8.11 (d, J=7.69 Hz, 1 H), 8.04 (s, 1 H), 7.95 (d, J=8.42 Hz,2 H), 7.81 (m, 5 H), 7.44 (m, 2 H), 7.26 (d, J=8.42 Hz, 1 H), 2.94 (s, 3 H) ppm. ESI mass spectrum analysis m/z (relative intensity): 546 (M+H, 100).

EXAMPLE 209 1-[3-amidinophenyl]-5-[(3-fluoro-2'-aminosulfonyl-[1,1']-biphen-4-yl) aminocarbonyl]3-trifluoromethyl pyrazole, trifluoroacetic acid salt

The nitrile prepared in Example 207 was subjected to standard Pinner reaction conditions and purification by reverse phase HPLC and freeze-drying afforded 0.042 g (25%) product. HRMS 547.117549 (calc'd), 547.117400 (obs).

EXAMPLE 210 1-(3-aminomethyl)phenyl-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl) carbonylmethyl]-3-trifluoromethyl pyrazole, trifluoroacetic acid salt

Part A. To the N-carbobenzyloxy protected carboxylic acid (5 g,11.9 mmol) (described in Example 207) in CH₂ Cl₂ (100 mL) was added oxalyl chloride (1.5 mL,16.7 mmol) and DMF (0.5 mL). The reaction was stirred 18 h, then the solvents were removed and the resultant yellow solid set aside. In a separate flask, dibromoethane (0.3 mL), was added to activated Zn (1.87 g,28 mmol) in THF (30 mL). The mixture was heated to reflux for 5 minutes, then cooled to 0° C. and 4-bromo-benzylbromide (5.96 g,24.9 mmol) in THF(45 mL) was added slowly over 0.5 h. The reaction was kept at 0° C. for 3 h, then cannulated into a mixture of CuCN (2.24 g,25 mmol), LiCl (1.52 g,36 mmol) and THF (15 mL) at -78° C. The reaction was warmed to -20° C. for 5 minutes, then recooled to -78° C. The solid acid chloride was suspended in THF(50 mL) and added to the above cold mixture. The reaction was kept at -78° C. for 1 h, 0° C. for 1 h, then at 20° C. for 1 h. The reaction was quenched with saturated. NH₄ Cl, filtered, and extracted with ethyl acetate. The aqueous layer was carefully acidified, extracted with ethyl acetate and the combined organic layers dried (Na₂ SO₄). Purification by chromatography on silica gel eluting with (1:1) hexanes/ethyl acetate and recrystalization (CH₂ Cl₂ /hexanes) afforded 2.8 g pure product and 2.5 g slightly impure product from the filtrate. ¹ HNMR(CDCl₃) δ: 7.47 (d, j=8.4 Hz, 2 H), 7.42 (m, 8 H), 7.08 (d, J=8.4 Hz, 2 H), 7.00 (d, J=8.4 Hz, 1 H), 5.13 (s, 2 H), 4.43 (d, J=5.9 Hz, 2 H), 4.09 (s, 2 H), 3.11 (AB, J=13.5, 46.9 Hz, 2 H) ppm; ESI (-ve) mass spectrum analysis m/z (relative intensity): 569.7-571.6 (M-H)⁺.

Part B. The product of Part A (0.5 g,0.88 mmol) was coupled by standard Suzuki procedures with 2-tert-butylaminosulfonylphenyl boronic acid (0.3 g, 1.1 mmol). Purification by chromatography on silica gel eluting with (2:1) hexanes/ethyl acetate afforded 0.36 g coupled product. Deprotection in boiling TFA (20 minutes), and purification by reverse phase HPLC and freeze drying afforded 0.2 g(64%) product. ¹ HNMR(DMSO-d₆) δ: 8.16 (m, 3 H), 8.13 (dd, J=6.9, 2.2 Hz, 1 H), 7.61 (m, 5 H), 7.45 (m, 1 H), 7.33 (m, 7 H), 4.45 (s, 2 H), 4.14 (d, J=5.9 Hz, 2 H) ppm; ESI mass spectrum analysis m/z (relative intensity): 514.8 (M+H, 100); Elemental Analysis calc'd for C₂₅ H₂₁ F₃ N₄ O₃ S (TFA) 1.3: C:50.02, H:3.39, N:8.45, found C:50.10, H:3.35, N:8.39.

EXAMPLE 211 1-(3-aminomethyl)phenyl-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl) aminocarbonyl]-3-(methylsulfonylmethyl)pyrazole, trifluoroacetic acid salt

Part A. The pyrazole (1 g, 3.92 mmol) obtained in part B of Example 10 was dissoved in CCl₄, then NBS (1.1 g, 6.27 mmol) and benzoylperoxide (0.038 g, 0.5 mmol) were added. The mixture was heated to reflux for 18 hr. After removal of the solvent, 50 mL water was added, then extracted with EtOAc, washed the organic layer with brine and dried over MgSO₄.

Filtration and concentration of the filtrate in vacuo was followed by purification using flash chromatography (2:3/Hexane:Methlene chloride) to afford 0.55 g of the desired bromomethyl product as a light yellow solid. ¹ HNMR(CDCl₃) δ: 7.77-7.69 (m, 3 H); 7.61 (t, J=7.69, 1 H); 7.13 (s, 1 H); 4.51 (s, 2 H); 4.32 (q, J=6.95, 2 H); 1.33 (t, J=6.96 3 H) ppm; Ammonia CI mass spectrum analysis m/z (relative intensity): 334.0 (97) and 336.0 (100).

Part B. To the product of part A (0.55 g, 1.65 mmol) in DMF was added KSMe (0.16 g, 1.81 mmol). The mixture was headed to reflux over night. The solution was quenched with water (100 mL) and extracted with EtOAc. The organic layer was washed with brine and dried over MgSO₄. Filtration, bubbling air through the filtrate for 2 h. and concentration of the filtrate in vacuo was followed by purification using flash chromatography (3:2/Hex:EtOAc) to afford 0.14 g methylsulfonylmethyl compound as a colorless oil. Ammonia CI mass spectrum analysis m/z (relative intensity): 334.1 (M+H, 100). ¹ HNMR(CDCl₃) δ: 7.77-7.69 (m, 4 H); 7.61 (t, J=8.05, 1 H); 4.38 (s, 2 H); 4.30 (q, J=6.96, 2 H); 2.94 (s, 3 H); 1.32 (t, J=6.96, 3 H) ppm.

Part C. Standard Weinreb coupling procedures of the product from part B with 2'-tert-butylaminosulfonyl-[1,1']-biphenyl aniline followed by the usual acid quench and silica gel flash chromatography afforded 0.13 g of the desired coupled product. ESI mass spectrum analysis m/z (relative intensity): 613.8 (75). ¹ HNMR(CDCl3) δ: 8.35 (s, 1 H); 8.16 (m, 1 H); 7.82 (s, 1 H); 7.75-7.55 (m, 8 H); 7.50-7.45 (m, 2 H); 7.30 (m, 1 H); 7.16 (S, 1 H); 4.42 (S, 2 H); 3.00 (s, 3 H); 1.02 (s, 9 H) ppm.

Part D. To the product from part C (0.13 g, 0.22 mmol) dissolved in ethanol (50 mL) was added 10% Pd/C (20 mg) and 2 mL AcOH. Hydrogenation of this solution on the Parr at 50 psi for 18 h followed by filtration through a pad of Celite and concentration afforded a crude reduced product which was treated TFA (6 mL) and heated to reflux for 50 min. After removal of the solvent and purification via standard HPLC reverse phase techniques and lyophilization afforded the title compound as a colorless solid. ESI mass spectrum analysis m/z (relative intensity): 540.1 (M+H, 100).

EXAMPLE 212 1-(3-amidino)phenyl-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl) aminocarbonyll-3-(methylaminosulfonylmethyl)pyrazole, trifluoroacetic acid salt.

Part A. To the product (1.1 g, 3.29 mmol) from part A (Example 211)) in DMF was added NaN₃ (0.24 g, 3.62 mmol). The mixture was stirred at R.T. for 18 h. The reaction mixture was quenched with water (200 mL) and extracted with EtOAc. Washed the organic layer with water and brine and dried over MgSO₄. The mixture was filtered and concentrated to afford 0.93 g of the crude azidomethyl compound. ESI mass spectrum analysis m/z (relative intensity): 297.1 (M+H, 100). ¹ HNMR (CDCl₃) δ: 7.77 (m, 3 H); 7.59 (m, 1 H); 7.08 (s, 1 H); 4.44 (s, 2 H); 4.30 (q, J=7, 2 H); 1.31 (t, J=7, 3 H) ppm.

Part B. To the product (0.54 g, 1.82 mmol) from part A in THF, was added PPh₃ (0.53 g, 2.01 mmol). The reaction mixture was stirred at rt for 4 h and the solvent was evaporated. HCl (1 N, 50 mL) was added and the organics were extracted with EtOAc. The organic layer was washed with brine and dried over MgSO₄. Evaporation in vacuo afforded the desired aminomethyl compound (0.32 g) as a white solid. ESI mass spectrum analysis m/z (relative intensity): 271.1 (M+H, 100). ¹ HNMR(CDCl₃) δ: 7.77 (s, 1 H); 7.72 (m, 2 H); 7.59 (m, 1 H): 7.01 (s, 1 H); 4.30 (q, J=7, 2 H); 3.96 (s, 2 H); 1.31 (t, J=7, 3 H) ppm.

Part C To the product (0.43 g, 1.59 mmol) from part B in CH₂ Cl₂ was added triethylamine (1.5 eq.). The reaction mixture was cooled to 0° C. and CH₃ SO₂ Cl (leq.) was added. The reaction mixture was stirred at R.T. for 18 hr. diluted with CH₂ Cl₂ and washed with 1 N HCl, NaHCO₃ (sat.), brine, then dried over MgSO₄. Evaporation in vacuo was followed by purification via flash chromatography (4:1/Hex:EtOAc) to afford 0.42 g of the desired methylsulfonamide pyrazole precursor. Ammonia CI mass spectrum analysis m/z (relative intensity): 349.0 (M+H, 100). ¹ HNMR(CDCl₃) δ: 7.76 (m, 2 H); 7.73 (m, 1 H); 7.61 (m, 1 H); 7.08 (s, 1 H); 4.44 (d, J=6.3, 2 H); 4.29 (q, J=7.3, 2 H); 3.325 (s, 1 H); 3.01 (s, 3 H); 1.31 (t, J=7.3, 3 H) ppm.

Part D Standard Weinreb coupling procedures of the product from part B with 2'-tert-butylaminosulfonyl-[1,1']-biphenylamine followed by the usual acid quench and silica gel flash chromatography afforded the desired coupled product. ESI (-ve) mass spectrum analysis m/z (relative intensity): 605.1 (M-H, 100). ¹ HNMR(CDCl₃) d:8.55 (s, 1 H); 8.16 (m, 1 H); 7.74 (m, 5 H); 7.56 (m, 6 H); 7.30 (m, 1 H); 7.02 (s, 1 H); 4.46 (d, 2 H); 3.81 (s, 1 H); 3.06 (s, 3 H); 1.04 (s, 9 H) ppm.

Part C Standard Pinner-amidine reaction protocol followed by purification via reverse phase HPLC techniques and lyophilization afforded the desired compound as colorless crystals. ¹ HNMR(CDCl₃) δ: 10.69 (s, 1 H); 9.43 (s, 2 H); 9.15 (s, 2 H); 8.05 (m, 1 H); 7.95 (s, 1 H); 7.85 (m, 1 H); 7.80 (m, 1 H); 7.70 (m, 4 H); 7.60 (m, 2 H); 7.35 (m, 2 H); 7.30 (m, 1 H); 7.20 (m, 3 H); 4.28 (d, J=6.1, 2 H); 2.97 (s, 3 H) ppm. ESI mass spectrum analysis m/z (relative intensity): 568.0 (100) HRMS for C₂₅ H₂₆ N₇ O₅ S₂ 2 568.143686 (calcd); 568.145471 (obs).

EXAMPLE 213 1- (3-aminomethylphenyl) -5-[(2'-aminosulfonyl-3-fluoro-[1,1']-biphen-4-yl) aminocarbonyl]-3-(methylaminosulfonylmethyl)pyrazole, trifluoroacetic acid salt

Part A Standard Weinreb coupling of the product from part C (Example 203) with 4-bromo-2-fluoroaniline afforded the desired amide. ¹ HNMR(CDCl₃) d:8.13 (t, J=8.4, 1 H); 7.90 (brd, 1 H); 7.79 (m, 1 H); 7.78 (m, 2 H); 7.61 (m , 1 H); 7.35 (m, 2 H); 6.96 (s, 1 H); 4.86 (m, 1 H); 4.44 (d, J=6.2, 2 H); 3.04 (s, 3 H) ppm. ESI (-ve) mass spectrum analysis m/z (relative intensity): 489.8 (85) and 491.8 (100).

Part B Standard Suzuki coupling of the product from part A with 2-thiomethylboronic acid afforded the desired 2'-thiomethyl-biphenyl intermediate. ¹ HNMR(CDCl3) δ: 8.25 (brd, 1 H); 8.00 (brd, 1 H); 7.83 (s, 1 H); 7.75 (m, 2 H); 7.62 (m, 1 H); 7.35 (m, 6 H); 6.96 (s, 1 H); 4.85 (m, 1 H); 4.48 (d, J=5.9, 2 H); 3.05 (s, 3 H); 2.39 (s, 1 H) ppm. ESI mass spectrum analysis m/z (relative intensity): 557.9 (M+Na, 100). ESI (-ve) mass spectrum analysis m/z (relative intensity): 533.8 (M-H, 100).

Part C To the product from part B (0.54 g, 1.01 mnol) in CH₂ Cl₂ was added MCPBA (0.52 g, 3.03 mmol) and the reaction mixture was stirred at R.T. for overnight. The mixture was then CH₂ Cl₂ and washed with NaHCO₃ (sat.), sodium bisulfite, brine and dried over MgSO₄. Filtration and concentration of the filtrate in vacuo was followed by purification using flash chromatography (1:1/Hex:EtOAc) to afford 0.53 g of the sulfonylmethyl derivative as white solid. ¹ HNMR(CDCl3) δ: 10.53 (s, 1 H); 8.07 (m, 1 H); 7.97 (s, 1 H); 7.85 (m, 1 H); 7.8 (m, 6 H); 7.41 (m, 1 H); 7.35 (m, 1 H); 7.23 (m, 2 H); 4.23 (s, 2 H); 2.94 (s, 3 H); 2.89 (s, 3 H) ppm. ESI (-ve) mass spectrum analysis m/z (relative intensity): 565.8 (70).

Part D The product from part C was hydrogenated as described previously to afford the desired benzylamine analog as colorless crystals following reverse phase HPLC and lyophilization techniques. ¹ HNMR(DMSO) δ: 10.53 (s, 1 H); 8.16 (brd, 2 H); 8.07 (m, 1 H); 7.75 (m, 1 H): 7.72 (m, 4 H); 7.49 (m, 5 H); 7.21 (m, 2 H): 4.23 (d, J=6.2, 2 H): 4.09 (m, 2 H): 2.93 (s, 3 H); 2.90 (s, 3 H) ppm. ESI mass spectrum analysis m/z (relative intensity): 571.9 (M+H, 100 ). HRMS calc'd for C26H27N5O5FS2 572.143766 (calcd); 572.145154 (obs).

EXAMPLE 214 1-(3-(N-carboxymethyl)amidinophenyl)-5-[(5-(2'-aminosulfonylphenyl) pyrimid-2-yl)aminocarbonyl]-3-methyl pyrazole, trifluoroacetic acid salt

To the Example 92 compound (100 mg, 0.19 mmol) in DMF was added methylchloroformate (36 mg, 0.38 mmol) and Et₃ N. The mixture was stirred at R.T. for 2.5 hr. Diluted with 100 mL water and extracted with EtOAc, the organic layer was washed with water, brine and dried over MgSO₄, filtered and concentrated in vacuo and purified using reverse phase HPLC techniques to afford the the desired carbamate [ESI mass spectrum analysis m/z (relative intensity): 590.9 (100)], which was then treated with TFA and heated to gentle reflux for 0.5 h. Evaporation of the TFA followed by purification via HPLC reverse phase and lyophilization afforded the title compound. ¹ HNMR(DMSO) δ: 11.34 (S, 1 H); 8.61 (s, 2 H); 8.01 (m, 1 H); 7.95 (m, 1 H): 7.80 (m, 1 H); 7.69 (m, 1 H); 7.64 (m, 3 H); 7.49 (s, 2 H); 7.40 (m, 1 H); 7.03 (s, 1 H): 3.79 (s, 3 H); 2.28 (s, 3 H) ppm. ESI mass spectrum analysis m/z (relative intensity): 535.0 (M+H, 100). HRMS calc'd for C₂₄ H₂₂ N₈ O₃ S 535.151213 (calcd); 535.151600 (obs).

EXAMPLE 215 1-(3-aminomethylphenyl)-5-[(2'-methylsulfonyl-[1,1']-biphen-4-yl) aminocarbonyl]-3-methylpyrazole, trifluoroacetic acid salt

Part A: Standard Weinreb coupling of 2' sulfonylmethyl-biphenylamine to the pyrazole ester obtained in part B of Example 10 followed by standard workup afforded after silica gel purification the desired coupled amide precursor. ¹ HNMR(CDCl₃) δ: 8.24 (d, J=7.7, 1 H); 7.87 (s, 1 H); 7.81 (s, 1 H); 7.76 (m, 1 H); 7.69 (m, 6 H); 7.45 (m, 2 H); 7.35 (m, 1 H); 6.71 (s, 1 H); 2.68 (s, 3 H); 2.42 (s, 3 H) ppm. ESI mass spectrum analysis m/z (relative intensity):478.9 (M+Na,100). ESI (-ve) mass spectrum analysis m/z (relative intensity): 454.9 (M-H, 100).

Part B: To the product from from part A(0.48 g, 1.05 mmol) in EtOH was added 10% Pd/C (80 mg) and 1 mL TFA. The mixture was hydrogenated on a Parr apparatus at 50 psi for 18 hr. After filteration through a pad of Celite and concentration the filtrate in vacuo, purified using reversed phase prep HPLC to afford the title compound. ¹ HNMR(DMSO) δ: 10.65 (s, 1 H): 8.17 (brd, 2 H): 8.06 (d, J=7,7, 1 H); 7.75 (m, 5 H); 7.49 (m, 6 H); 6.92 (s, 1 H); 4.10 (m, 2 H); 2.81 (s, 3 H): 2.29 (s, 3 H) ppm. ESI mass spectrum analysis m/z (relative intensity): 460.9 (M+H, 100). HRMS calc'd for C₂₅ H₂₅ N₄ O₃ S 461.164738 (calcd); 461.164405 (obs).

EXAMPLE 216 1-(3-aminomethylphenyl)-5-(2'-aminosulfonyl-3-methyl-[1,1']-biphen-4-yl) aminocarbonyl]-3-trifluoromethyl pyrazole. trifluoroacetic acid salt

Part A: Standard Weinreb coupling of 2'-tert-butylaminosulfonyl-2-methyl-biphenylamine with the previously obtained pyrazole ester afforded the desired coupled amide precursor. ¹ HNMR(CDCl₃) δ: 8.17 (d, J=7.7, 1 H); 7.83 (m, 4 H): 7.64 (M, 2 H): 7.56 (m, 2 H): 7.4 (m, 3 H); 7.15 (s, 1 H); 3.61 (s, 1 H): 2.36 (s, 3 H); 1.04 (s, 9 H) ppm. ESI mass spectrum analysis m/z (relative intensity): 604.1 (M+Na, 100). ESI (-ve) mass spectrum analysis m/z (relative intensity): 580.3 (M-H, 100).

Part B: Reduction of the benzonitrile to the benzylamine followed by removal of the tert-butyl group and standard reverse phase HPLC purification afforded the title compound. ¹ HNMR(DMSO) δ: 10.33 (s, 1 H); 8.23 (bd, 2 H); 8.02 (m, 1 H); 7.76 (s, 1 H); 7.66 (m, 6 H); 7.40 (d, J=8.1, 1 H); 7.31 (m, 5 H): 4.15 (m, 2 H); 2.25 (s, 3 H) ppm. ESI mass spectrum analysis m/z (relative intensity): 530.2 (M+H, 100).

EXAMPLE 217 1-(3-aminomethylphenyl)-5-[(3-fluoro-2'-methylsulfonyl-[1,1']-biphen-4-yl) aminocarbonyl]-1,2,3-triazole. trifluoroacetic acid salt

Standard Weinreb coupling of 4-bromo-2-fluoro-aniline with the previously obtained 1,2,3-triazole-5-carboxylic acid as used in the preparation of Example 46 afforded after purification via flash silica-gel chromatography the coupled amide triazole derivative. ¹ HNMR(CDCl₃) d:8.23 (s, 1 H); 8.11 (m, 1 H); 7.86 (m, 4 H); 7.68 (m, 1 H); 7.34 (m, 2 H) ppm. ESI (-ve) mass spectrum analysis m/z (relative intensity): 383.8 (100) and 385.7 (80). Standard Suzuki coupling of this intermediate with 2-thiomethyl boronic acid followed by oxidation with MCPBA in dichloromethane afforded the desired biphenylsulfonyl derivative. ¹ HNMR(CDCl₃) δ: 8.34 (m, 3 H); 8.05 (bd, 1 H); 7.93 (m, 3 H); 7.74 (m, 3 H); 7.37 (m, 2 H); 7.24 (m, 1 H); 2.74 (s, 3 H) ppm. ESI (-ve) mass spectrum analysis m/z (relative intensity): 459.9 (M-H, 100). This intermediate was then reduced to the benzylamine and purified via standard conditions described previously. ¹ HNMR(DMSO) δ: 10.76 (s, 1 H); 8.53 (s, 1 H); 8.21 (bd, 2 H); 8.05 (m, 1 H); 7.77 (m, 7 H); 7.39 (m, 2 H); 7.22 (m, 1 H); 4.14 (m, 2 H); 2.89 (s, 3 H) ppm. ESI (-ve) mass spectrum analysis m/z (relative intensity): 465.9 (M+H, 100). HRMS calc'd for C₂₃ H₂₁ N₅ O₃ FS, 466.134915, found 466.136900.

EXAMPLE 218 1-(3-aminomethyl-4-methyl)phenyl-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl) aminocarbonyl]-3-methylpyrazole. trifluoroacetic acid salt

Part A: To a cold (0° C.) acidic (Con HCl, 100 mL) solution of 2-methyl-4-amino-benzonitrile(10 g, 78.12 mmoL) was added sodium nitrite (8.08 g, 117.19 mmoL) previously dissolved in water (20 mL). The reaction temperature was kept cold throughout the addition of sodium nitrite. After stiring for an additional 0.5 h a solution of SnCl₂ in con HCl(50 mL) was added dropwise. A precipitate immediately ensued. The reaction mixture was allowed to stirr at 0° C. for an additional 18 h then filtered, washed with cold water (1000 mL) followed by a solution of Petroleum ether/ether(2:1,500 mL). The residue was dried in vacuo overnight to afford a total weight of 8.15 g crude hydrazine tin salt.

Part B: The tin salt obtained in part A was stirred in glacial acetic acid (100 mL). To this solution was then added methoxy-oxime derived from ethyl 2,4-dioxovalerate (4.59 g, 24.55 mmoL). The reaction mixture was gently refluxed overnight. Acetic acid was evaporated off and the residue was then quenched with water (200 mL). The organics were extracted with ethyl acetate (2×100 mL) washed with saturated sodium bicarbonate (2×50 mL), brine (50 mL) and dried (magnesium sulfate). Column chromatography (silica gel, ethyl acetate:hexane 2:8) then afforded the desired pyrazole carboxylate (4 g) as a pale yellow oil which crystallized on standing.

Part C: The product from part B was then subjected to the standard Weinreb trimethylaluminum coupling protocol with 2'-tert-butylaminosulfonyl-[1,1']-biphen-4-yl-amine as described previously. The crude was then subjected to silica gel column chromatography (methylene chloride:methanol, 9:1) to afford pure material in 90% yield. ¹ HNMR(CDCl₃) δ: 8.30 (bs, 1 H), 8.13 (bd, 1 H), 7.78-7.23 (m, 10 H), 6.78 (s, 1 H), 3.68 (s, 1 H), 2.60 (s, 3 H), 2.40 (s, 3 H), 1.01 (s, 9 H) ppm; ESI mass spectrum analysis m/z (relative intensity) 528 (M+H, 100).

Part D: The product from part D was then subjected reduction (Parr apparatus) at 50 psi hydrogen pressure in an acidic media (methanol, acetic acid) using 10% palladium on carbon overnight. The solvents were evaporated and the crude was then stirred in TFA (reflux) for 0.5 h. Evaporation of the solvents then afforded crupe benzylamine product which was then subjected to a preparative HPLC purification technique (acetonitrile:water, gradient containing 5% TFA) to afford the desired benzylamine as flaky colorless crystals. ¹ HNMR(DMSO-d₆) δ: 10.6 (s, 3 H), 8.14 (bs, 2 H), 8.01 (d, 1 H), 7.68 (d, 2 H), 7.64-7.54 (m, 2 H), 7.38-7.26 (m, 5 H), 6.91 (s, 1 H), 4.07 (bd, 2 H), 2.38 (s, 3 H), 2.33 (s, 3 H) ppm; ESI mass spectrum analysis m/z(relative intensity) 476.2 (M+H, 100).

EXAMPLE 219 1-(3-aminomethyl-4-fluoro)phenyl-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl) aminocarbonyl]-3-methylpyrazole, trifluoroacetic acid salt

The pyrazole compound was prepared from readily accessible 4-fluoro-3-cyano-phenylhydrazine.tin salt (obtained from the corresponding aniline) and the oxime derived from ethyl-2,4-dioxovalerate via procedures described previously. Standard Weinreb coupling of the pyrazole with 2'-tert-butylaminosulfonyl-[1,1']-biphen-4-yl-amine afforded the desired coupled amide presursor which was then subjected to the standard reductive protocol (50 psi hydrogen pressure,, methanol:acetic acid) using 10% palladium on carbon.

Evaporation of the solvents followed by treatment with TFA for 0.5 h and then preparative HPLC as described before afforded the title compound as colorless crystals. ¹ HNMR(DMSO-d₆) δ: 8.25 (bs, 3 H), 8.00 (d, 1 H), 7.78-7.23 (cp, 12 H), 6.95 (s, 1 H), 4.14 (m, 2 H), 2.30 (s, 3 H) ppm. ESI mass spectrum analysis m/z (relative intensity) 480.2 (M+H, 100).

EXAMPLE 220 1-(3-aminomethyl-4-chloro)phenyl-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-methylpyrazole, trifluoroacetic acid salt

The pyrazole compound was prepared from readily accessible 4-chloro-3-cyano-phenylhydrazine tin salt (obtained from the corresponding aniline) and the oxime derived from ethyl-2,4-dioxovalerate via procedures described previously. ¹ HNMR(CDCl₃) δ: 7.78 (d, 1 H), 7.86-7.55 (m, 2 H), 6.86 (s, 1 H), 4.24 (q, 2 H), 2.35 (s, 3 H), 1.28 (t, 3 H) ppm; ESI mass spectrum analysis m/z(relative intensity) 290 (M+H, 100). Standard Weinreb coupling of the pyrazole obtained above with 2'-tert-butylaminosulfonyl-[1,1']-biphen-4-yl-amine afforded the desired coupled amide presursor which was then subjected to the treatment with tetrabutylammonium borohydride (1.5 equiv.) in dichloromethane for 24 h. The solvent was evaporated and the residue was then gently refluxed in TFA for 0.5 h. Evaporation of the solvent followed by preparative HPLC as described before afforded the title compound as colorless crystals: ¹ HNMR(DMSO-d₆) δ: 8.25 (bs, 3 H), 8.00 (d, 1 H), 7.78-7.23 (cp, 12 H), 6.95 (s, 1 H), 4.14 (m, 2 H), 2.30 (s, 3 H) ppm. ESI mass spectrum analysis m/z(relative intensity) 497.1 (M+H, 100).

EXAMPLE 221 1-(3-aminomethyl-4-fluoro)phenyl-5-[(2'-aminosulfonyl-3-fluoro-[1,1']-biphen-4-yl)aminocarbonyl]-3-trifluoromethylpyrazole, trifluoroacetic acid salt

The reduction of the benzonitrile precursor prepared as described before (10% palladium on carbon, methanol/acetic acid at 50 psi hydrogen) afforded the title compound as colorless crystals after preparative HPLC purification and lyophilization techniques. ¹ HNMR(DMSO-d₆) δ: 10.68 (s, 1 H), 8.27 (bs, 2 H), 8.02 (dd, 1 H), 7.81 (m, 1 H), 7.73 (s, 1 H), 7.68-7.60 (m, 4 H), 7.61-7.43 (m, 3 H), 7.38-7.30 (m, 2 H), 7.20 (dd, 2 H), 4.18 (bd, 2 H) ppm; ESI mass spectrum analysis m/z(relative intensity) 551.9 (M+H,100).

EXAMPLE 222 1-(3-aminomethyl)phenyl-5-[(2'-aminosulfonyl-3-fluoro-[1,1']-biphen-4-yl)aminocarbonyl]-3-methylpyrazole, trifluoroacetic acid salt

Part A: The coupling of ethyl 1-(3-cyanophenyl)-3-methyl-5-carboxylate with 2'-tert-butylaminosulfonyl-3-fluoro-[1,1']-biphen-4-yl-amine via the Weinreb protocol as described previously afforded the desired coupled amide compound. In this case 1.5 equivalents of the biphenyl analog was used to facilitate the coupling. Purification via silicagel(methylene chloride/methanol, 9/1) afforded pure amide (60%) as a pale yellow oil. ¹ HNMR(CDCl₃) δ: 8.35 (t, 1 H), 8.15 (dd, 1 H), 7.96 (m, 1 H), 7.82 (s, 1 H), 7.78-7.68 (m, 4 H), 7.60-7.48 (m, 4 H), 7.20 (m, 1 H), 6.74 (s, 1 H), 3.67 (s, 1 H), 2.04 (s, 3 H), 1.04 (s, 9 H) ppm; ESI mass spectrum analysis m/z(relative intensity) 553.9 (M+Na, 100). ESI (-ve) mass spectrum analysis m/z(relative intensity) 529.9 (M-H, 100).

Part B: The product obtained from part A was then converted to the corresponding benzylamine via the reductive methodology (10% Pd/C, MeOH/AcOH at 50 psi hydrogen pressure) described previously. Evaporation of the solvent followed by standard removal of the tert-butyl group with TFA and purification via preparative HPLC techniques afforded pure title compound as colorless crystals (60%). ¹ HNMR(DMSO-d₆) δ: 10.42 (s, 1 H), 8.20 (bs, 2 H), 8.02 (dd, 1 H), 7.70-7.59 (m, 4 H), 7.55-7.29 (m, 6 H), 7.19 (dd, 1 H), 6.97 (s, 1 H), 4.11 (bd, 2 H), 2.50 (s, 2 H) ppm; ESI mass spectrum analysis m/z(relative intensity) 480 (M+H, 100).

EXAMPLE 223 1-(3-aminomethyl)phenyl-5-[(3-fluoro-2'-methylsulfonyl-[1,1']-biphen-4-yl) aminocarbonyl]-3-trifluoromethylpyrazole, trifluoroacetic acid salt

Part A: The coupling of ethyl 1-(3-cyanophenyl)-3-methyl-5-carboxylate with 2'-methylsulfonyl-3-fluoro-[1,1']-biphen-4-yl-amine (previously prepared via the Suzuki coupling methodology of 2-thiomethylphenylboronic acid with 4-bromo-2-fluoro aniline) via the Weinreb protocol as described previously afforded the desired coupled amide compound. Purification via silica gel (methylene chloride/methanol, 9/1) afforded pure amide (80%) as a colorless solid. The amide was also obtaine by first coupling (Weinreb) of 2-fluoro-4-bromo-aniline with the above pyrazole carboxylate followed by Suzuki coupling with 2-thiomethyl-phenylboronic acid and oxidation to the sulfonyl derivative. ¹ HNMR(CDCl₃) δ: 8.39 (t, 1 H), 8.20 (dd, 1 H), 7.96 (bd, 1 H), 7.83 (s, 1 H), 7.78-7.59 (m, 5 H), 7.41-7.35 (t, 2 H), 7.17 (d, 1 H), 6.74 (s, 1 H), 2.73 (s, 3 H), 2.40 (s, 3 H) ppm; ESI mass spectrum analysis m/z(relative intensity) 593 (M+Na, 100). ESI (-ve) mass spectrum analysis m/z(relative intensity) 572 (M-H, 100).

Part B: Reduction of the product from part A via procedures described previously and HPLC purification afforded the desired compound as colorless crystals (70%). ¹ HNMR(DMSO-d₆) δ: 10.45 (s, 1 H), 8.20 (bs, 3 H), 8.08 (dd, 1 H), 7.80-7.66 (m, 4 H), 7.55-7.37 (m, 5 H), 7.21 (dd, 1 H), 6.98 (s, 1 H), 4.12 (s, 2 H), 2.94 (s, 3 H), 2.50 (s, 3 H) ppm; ESI mass spectrum analysis m/z (relative intensity) 479 (M+H, 100).

EXAMPLE 224 1-(3-amidinophenyl)-3-methyl-5-[(3-fluoro-4-(N-morpholino)phenyl) aminocarbonyl]pyrazole bis-trifluoroacetate

Part A. Preparation of N-(3-fluoro-4-nitrophenyl)morpholine. 3,4-Difluoronitrobenzene (10.0 g, 62.86 mmol) was dripped into a cooled solution(0° C.) of morpholine (6.03 mL, 69.14 mmol), diisopropylamine (11.83 mL, 67.89 mmol) and 35 mL ethyl acetate over 1.5 H. The reaction mixture was allowed to warm to ambient temperature over 48 H. Diluted reaction mixture with 25 mL methylene chloride, 100 mL ethyl acetate and 50 mL water. Separated and extracted aqueous 2×25 mL EtOAc. Combined oraganics, dried over magnesium sulfate and concentrated under reduced pressure to give a yellow solid. The crude material was recrystallized from acetone and water to give 12.55 g of a yellow crystalline solid. ¹ HNMR(DMSO-d6) δ: 7.99 (m, 2 H) 7.14 (t, 1 H, J=8.79 Hz) 3.71 (bt, 4 H, J=4.56 Hz) 3.23 (bt, 4 H, J=4.76 Hz). ESI mass spectrum analysis m/z(relative intensity) 227 (M+H).

Part B. Preparation of N-(3-fluoro-4-aminophenyl)morpholine.

N-(3-fluoro-4-nitrophenyl)morpholine (6.01 g,26.59 mmol) and a catalytic amount of palladium on carbon(10%) were suspended in 100 mL methanol in a Parr flask. The reaction mixture was placed on the Parr Hydrogenator at 60 psi for 2 H. The reaction mixture was passed through a Celite pad and the filtrate was concentrated under reduced pressure to give 4.50 g of N-(3-fluoro-4-aminophenyl)morpholine an off-colored solid. ¹ HNMR(DMSO-d6) δ: 6.73 (t, 1 H, J=9.34), 6.28 (m, 2 H), 3.64 (bt, 4 H, J=4.58 Hz), 2.76 (bt, 4 H, J=4.58 Hz). ESI mass spectrum analysis m/z(relative intensity) 197 (M+H, 100). ¹⁹ FNMR(DMSO-d6) δ: -124.455.

Part C. Preparation of 1-(3-cyanophenyl)-3-methyl-5-((3-fluoro-4-(N-morpholino)phenyl)aminocarbonyl)pyrazole.

Dimethylaminopyridine (0.28 g,2.25 mmol) was added to a solution of 1-(3-cyanophenyl)-3-methyl-pyrazole-5-carboxylic acid chloride (0.46 g,1.88 mmol) and N-(3-fluoro-4-aminophenyl)morpholine (0.37 g,1.88 mmol) in 20 mL methylene chloride. The reaction mixture was stirred at ambient temperature for 72 H and then concentrated under reduced pressure. The resulting residue was purified via flash chromotography to give 0.070 g of pure 1-(3-cyanophenyl)-3-methyl-5-((3-fluoro-4-(N-morpholino)phenyl)aminocarbonyl)pyrazole. ¹ HNMR(DMSO-d6) δ: 10.50 (s, 1 H) 7.93 (s, 1 H), 7.83 (d, 1 H, J=7.33 Hz), 7.73 (d, 1 H, J=8.79 Hz), 7.62 (t, 1 H, J=7.87 Hz), 7.53 (m, 1 H), 7.34 (d, 1 H, J=9.15 Hz), 6.99 (t, 1 H, J=9.34 Hz), 6.93 (s, 1 H), 3.69 (bt, 4 H, J=4.58 Hz), 2.92 (bt, 4 H, J=4.58 Hz), 2.28 (s, 3 H). ESI mass spectrum analysis m/z(relative intensity) 406 (M+H, 100), 833 (2M+Na). ¹⁹ F NMR (dmso-d6,300 MHz) δ: -122.081.

Part D. Preparation of 1-(3-amidinophenyl)-3-methyl-5-((3-fluoro-4-(N-morpholino)phenyl)aminocarbonyl)pyrazole.

1-(3-Cyanophenyl)-3-methyl-5-((3-fluoro-4-(N-morpholino)phenyl)aminocarbonyl)pyrazole (0.070 g,0.173 mmol) was dissovled in 2 mL chloroform and 2 mL ethanol at 0° C. Hydrogen chloride gas was bubbled into the reaction mixture for 1 H. The reaction mixture was allowed to warm to ambient temperature over 15H and was concentrated under reduced pressure. The resulting solid was placed under high vacuum for 2 H. Then the crude imidate was dissolved in 2 mL ethanol and ammonium carbonate(025 g,2.60 mmol) was added to the solution at ambient temperature. The reaction mixture was stirred for 72 H and concentrated under reduced pressure. The crude product was purified by standard HPLC methods to give 0.016 g of pure 1-(3-amidinophenyl)-3-methyl-5-((3-fluoro-4-(N-morpholino) phenyl) aminocarbonyl) pyrazole. ¹ HNMR (DMSO-d6) δ: 10.53 (s, 1 H), 9.40 (s, 2 H), 9.12 (s, 2 H), 7.93 (d, 1 H, J=1.71 Hz, 2 H), 7.81 (m, 1 H), 7.70 (m, 2 H), 7.53 (dd, 1 H, J=15 Hz), 7.35 (d, 1 H, J=8.79 Hz), 7.01 (m, 2 H), 3.72 (bt, 4 H, J=4.52 Hz), 2.95 (bt, 4 H, J=4.6 Hz), 2.29 (s, 3 H). ESI mass spectrum analysis m/z(relative intensity) 423 (M+H,100). ¹⁹ FNMR(DMSO-d6) δ: -73.790 and -121.040. HRMS Calculated for C22H24N6O2F1: 423.194478, found 423.192755.

EXAMPLE 225 1-(3-aminomethylphenyl)-3-methyl-5-[(3-fluoro-4-(N-morpholino)phenyl)aminocarbonyl]pyrazole bis-trifluoroacetate

Part A. Preparation of 1-(3-cyanophenyl)-3-methyl-5-((3'-fluoro-4'-(N-morpholino)phenyl)aminocarbonyl)pyrazole.

Dimethylaminopyridine(0.18 g,1.47 mmol) was added to a solution of N-(cyanophenyl)-3-methyl-pyrazole-5-carboxylic acid chloride(0.30 g,1.22 mmol) and previously described N-(3-fluoro-4-aminophenyl)morpholine(0.24 g,1.22 mmol) in 20 mL methylene chloride. The reaction mixture was stirred at ambient temperature for 72 H and then concentrated under reduced pressure. The resulting residue was purified via flash chromotography to give 0.070 g of pure 1-(3-cyanophenyl)-3-methyl-5-((3'-fluoro-4'-(N-morpholino)phenyl)aminocarbonyl)pyrazole. ¹ HNMR(DMSO-d6) δ: 10.50 (s, 1 H), 7.93 (s, 1 H), 7.83 (d, 1 H, J=7.33 Hz), 7.73 (d, 1 H, J=8.79 Hz), 7.62 (t, 1 H, J=7.87 Hz), 7.53 (m, 1 H), 7.34 (d, 1 H, J=9.15 Hz), 6.99 (t, 1 H, J=9.34 Hz), 6.93 (s, 1 H), 3.69 (bt, 4 H, J=4.58 Hz), 2.92 (bt, 4 H, J=4.58 Hz), 2.28 (s, 3 H). ESI mass spectrum analysis m/z(relative intensity) 406 (M+H, 100) 833 (2M+Na). ¹⁹ F NMR (DMSO-d6) δ: 122.078.

Part B. Preparation of 1-(3-aminomethylphenyl)-3-methyl-5-((3'-fluoro-4'-(N-morpholino)phenyl)aminocarbonyl)-pyrazole.

1-(3-Cyanophenyl)-3-methyl-5-((3'-fluoro-4'-(N-morpholino)phenyl)aminocarbonyl)pyrazole(0.21 g,0.519 mmol) was suspended with a catalytic amount of palladium on carbon(10%) in 15 mL methanol and 1 mL trifluoroacetic acid. The reaction mixture was placed on the Parr Hydrogenator at 60 psi for 20 H. The reaction mixture was passed through a Celite pad and the filtrate was concentrated under reduced pressure. The crude material was purified by standard HPLC methods to give pure 1-(3-aminomethylphenyl)-3-methyl-5-((3'-fluoro-4'-(N-morpholino)phenyl)aminocarbonyl)pyrazole. ¹ HNMR(DMSO-d6) δ: 10.53 (s, 1 H), 8.18 (bs, 2 H), 7.60 (s, 1 H), 7.53 (dd, 1 H, J₁ =15.0 Hz, J₂ =2.2 Hz), 7.44 (m, 2 H), 7.33 (d,2 H, J=7.33 Hz), 6.98 (dd, 1 H, J₁ =9.3 Hz, J₂ =9.2 Hz), 6.86 (s, 1 H) 4.07 (bt, 2 H, J₁ =2.9 Hz, J₂ =2.6 Hz), 3.69 (bt, 4 H, J₁ =4.4 Hz, J₂ =4.8 Hz), 2.91 (bt, 4 H, J₁ =4.9 Hz, J₂ =4.8 Hz), 2.47 (s, 3 H). ESI mass spectrum analysis m/z(relative intensity) 410 (M+H, 100). ¹⁹ F NMR (DMSO-d6) δ: -74.991 and -122.105. HRMS calculated for C22H25N5O2F: 410.199224, found 410.197598.

EXAMPLE 226 1-(3-aminomethylphenyl)-3-trifluoromethyl-5-((3-fluoro-4-(2-methylimidazol-1-yl)phenyl)aminocarbonyl)pyrazole bis-trifluoroacetate

Part A. Preparation of 3-fluoro-4-(2-methylimidazol-1-yl)nitro-benzene.

2-Methylimidazole(1.0 g,12.18 mmol) was added to a solution of 3,4-difluoronitrobenzene in 100 mL DNF. Added potassium carbonate(2.02 g,14.61 mmol) to the reaction mixture and stirred vigorously for 24 H. Concentrated reaction mixture under reduced pressure and took up residue in 100 mL ethyl acetate. Washed organics 6×50 mL water and 3×50 mL brine solution. Dried resulting organics over magnesium sulfate and concentrated resulting organics under reduced pressure to give 1.66 g of crude 3-fluoro-4-N-(2-methylimidazol-1-yl)nitro-benzene. ¹ HNMR(dmso-d6,300 MHz) δ: 8.42 (dd, 1 H, J₁ =2.4 Hz, J₂ =10 Hz), 8.21 (m, 1 H), 7.86 (t, 1 H, J=8.4), 7.34 (s, 1 H), 6.98 (s, 1 H), 2.21 (s, 1 H). ESI mass spectrum analysis m/z(relative intensity) 221.9 (M+H, 100). ¹⁹ F NMR (DMSO-d6) δ: -118.512.

Part B. Preparation of 3-fluoro-4-(2-methylimidazol-1-yl) aniline.

3-Fluoro-4-N-(2-methylimidazol-1-yl)nitrobenzene (1.66 g,7.51 mmol) was added to a suspension of palladium on carbon(10%) in 30 mL menthanol. The reaction mixture was placed on the Parr Hydrogenator at 60 psi for 20 H. Filtered reaction mixture through a Celite pad and concentrated filtrate under reduced pressure to give 1.40 g of the crude 3-fluoro-4-N-(2-methylimidazol-1-yl)aniline. ¹ HNMR(dmso-d6,300 MHz) δ: 7.02 (m, 2 H), 6.83 (s, 1 H), 6.43 (m, 2 H), 5.70 (bs, 1 H), 2.07 (s, 3 H). ESI mass spectrum analysis m/z(relative intensity). ¹⁹ F NMR (DMSO-d6) δ: -124.344.

Part C. Preparation of 1-(3-cyanophenyl)-3-trifluoromethyl-5-((3'-fluoro-4'-(2-methylimidazol-1-yl)phenyl)-aminocarbonyl)pyrazole.

Dimethylaminopyridine(0.19 g,1.56 mmol) was added to a solution of N-(3-cyanophenyl)-3-trifluoromethyl-pyrazole-5-carboxylic acid chloride(O.39 g,1.30 mmol) and 3-fluoro-4-(2-methylimidazol-1-yl)aniline(0.25 g,1.30 mmol) in 10 mL methylene chloride. The reaction mixture was stirred at ambient temperature for 5 H and then concentrated under reduced pressure. The resulting residue was purified via flash chromatography to give 0.16 g of pure 1-(3-cyanophenyl)-3-trifluoromethyl-5-((3'-fluoro-4'-(2-methylimidazol-1-yl) phenyl)-aminocarbonyl)pyrazole. ESI mass spectrum analysis m/z(relative intensity) 455.2 (M+H, 100).

Part D. Preparation of 1-(3-aminomethylphenyl)-3-trifluoro-methyl-5-((3'-fluoro-4'-(2-methylimidazol-1-yl)phenyl)aminocarbonyl)pyrazole bis-trifluoroacetate.

Standard transformation of the benzonitrile(O.16 g, 0.344 mmol) obtained in part C to the benzylamine via catalytic hydrogenation yeilded 0.050 g 1-(3-methylaminophenyl)-3-trifluoromethyl-5-((3'-fluoro-4'-(2-methylimidazol-1-yl)phenyl)aminocarbonyl)pyrazole bis-trifluoroacetate after HPLC purification. ¹ HNMR(DMSO-d6) δ: 11.25 (s, 1 H), 7.91-7.52 (m, 10 H), 4.12 (m, 2 H), 2.43 (s, 3 H). ESI mass spectrum analysis m/z(relative intensity) 459.1 (M+H, 100). HRMS(NH3-CI): Calculated for C22H19N6OF4: 459.155647, found 459.154688.

EXAMPLE 227 1-(3-cyanophenyl)-3-trifluoromethyl-5-(([1,1']-biphen-4-yl)oxymethyl)pyrazole

Part A. Preparation of 1-(3-cyanophenyl)-3-trifluoromethyl-5-(([1,1']-biphen-4-yl)oxymethyl)pyrazole.

Diethylazodicarboxylate (0.41 mL,2.59 mmol) was dripped into a solution of previously described 1-(3-cyanophenyl)-3-trifluoromethyl-5-hydroxymethylpyrazole (0.46 g,1.73 mmol), 4-hydroxy-[1,1']-biphenyl (0.44 g,2.59 mmol), and triphenylphosphine (0.68 g, 2.59 mmol) in 15 mL THF over 1 H. Let reaction mixture stir for 48 h. Diluted reaction mixture with 30 mL water and extracted with ethyl acetate. Combined organics, dried over magnesium sulfate and purified crude material by flash chromatography to give 0.040 g of pure 1-(3-cyanophenyl)-3-trifluoromethyl-5-(([1,1']-biphen-4-yl)oxymethyl) pyrazole. ¹ HNMR(DMSO-d6) δ: 8.01 (m, 1 H), 7.91 (m, 1 H), 7.75 (m, 1 H), 7.58 (m, 4 H), 7.44 (m, 2 H), 7.34 (m, 1 H), 6.99 (m, 2 H), 6.88 (s, 1 H), 5.05 (s, 2 H). ESI mass spectrum analysis m/z(relative intensity) 420 (M+H,100), 437 (M+NH4,63).

EXAMPLES 228 AND 229 1-(3-amidinophenyl)-3-trifluoromethyl-5-[([,1,1']-biphen-4-yl)oxymethyl]pyrazole (Example 228) and i-(3-Carboxamidophenyl)-3-trifluoromethyl-5-(([1,1']-biphen-4-yl)oxymethyl)pyrazole (Example 229)

Part A. Preparation of 1-(3-amidinophenyl)-3-trifluoromethyl-5-(([1,1']-biphen-4-yl)oxymethyl)pyrazole and 1-(3-carboxamidophenyl)-3-trifluoromethyl-5-(([1,1']-biphen-4-yl)oxymethyl)pyrazole.

Standard Pinner-amidine transformation of the 1-(3-cyanophenyl)-3-trifluoromethyl-5-(([1,1']-biphen-4-yl)oxymethyl)pyrazole as previously described afforded 0.022 g of 1-(3-amidinophenyl)-3-trifluoromethyl-5-(([1,1']-biphen-4-yl)oxymethyl)pyrazole trifluoroacetate. ¹ HNMR(DMSO-d6) δ: 9.42 (bs, 2 H), 9.16 (bs, 2 H), 8.06 (s, 1 H), 8.01 (d, 1 H, J=8.1 Hz), 7.91 (d, 1 H, J=8.1 Hz), 7.79 (t, 1 H, J=8.1 Hz), 7.56 (m, 4 H),7.39 (m, 2 H), 7.28 (m, 1 H), 7.23 (m, 1 H), 7.01 (d, 2 H, J=8.79 Hz), 5.26 (s, 2 H). ESI mass spectrum analysis m/z(relative intensity) 437 (M+H, 100). HRMS(NH3-CI): Calculated for C24H20N4OF3: 437.158921, found 437.157809 and 0.002 g of 1-(3-carboxamidophenyl)-3-trifluoromethyl-5-(([1,1']-biphen-4-yl)oxymethyl)pyrazole after HPLC purification. ¹ HNMR(dmso-d6,300 MHz) δ: 8.18 (s, 1 H) 7.99 (d, 1 H, J=7.7 Hz), 7.78 (d, 1 H, J=9.2 Hz), 7.68-7.53 (m, 5 H), 7.39 (t, 2 H, J=7.7 Hz), 7.27 (dd, 2 H, J₁ =7.3 Hz, J₂ =7.0 Hz), 7.18 (s, 1 H), 7.01 (d, 2 H, J=8.8 Hz), 5.21 (s, 2 H). ESI mass spectrum analysis m/z(relative intensity) 479 (M+H+MeCN). HRMS(NH3-CI): Calculated for C24H20N4OF3: 437.15892, found 437.157809.

EXAMPLES 230 AND 231 1-(3-amidinophenyl)-3-trifluoromethyl-5-((2-fluoro-4-(N-morpholino)phenyl)aminocarbonyl)pyrazole bis-trifluoro acetate and 1-(3-Carboxamidophenyl)-3-trifluoromethyl-5-((2-fluoro-4-(N-morpholino)phenyl)aminocarbonyl) pyrazole

Part A. Preparation of 2-fluoro-4-(-N-morpholino)aniline.

Morpholine(10.0 mL,115 mmol) was added to a mixture of 4-bromo-2-fluoroaniline(1.03 g,5.42 mmol), copper(I) bromide (0.039 g,0.27 mmol) and potassium carbonate(1.50 g,10.84 mmol). The reaction mixture was heated to 130° C. for 48 h, concentrated under reduced pressure and purified by flash chromotography to afford 0.11 g of pure 2-fluoro-4-(-N-morpholino)aniline. ¹ HNMR(DMSO-d6) δ: 6.73 (dd, 1 H, J₁ =8.8 Hz, J₂ =9.9 Hz), 6.64 (dd, 1 H, J₁ =2.6 Hz, J₂ =13.2 Hz), 6.57 (m, 1 H), 3.85 (m, 4 H), 3.02 (m, 4 H). ESI mass spectrum analysis m/z(relative intensity) 197 (M+H, 100). ¹⁹ FNMR (dmso-d6,300 MHz) δ: -133.

Part B. Preparation of 1-(3-cyanophenyl)-3-trifluoromethyl-5-((2'-fluoro-4'-(N-morpholino)phenyl)aminocarbonyl)pyrazole.

2-Fluoro-4-(N-morpholino)aniline(0.11 g,0.56 mmol) in 5 mL methylene chloride was dripped into a stirring solution of N-(3-cyanophenyl)-3-trifluoromethyl-pyrazole-5-carboxylic acid chloride(0.17 g,0.56 mmol) and dimethylaminopyridine (0.082 g, 0.67 mmol) in 10 mL methylene chloride. The reaction mixture was stirred at ambient temperature for 20 h. The reaction mixture was concentrated under reduced pressure and purified by flash chromatography to give 0.19 g of pure 1-(3-cyanophenyl)-3-trifluoromethyl-5-[(2'-fluoro-4'-(N-morpholino)phenyl)aminocarbonyl]pyrazole. ¹ HNMR(DMSO-d6) δ: 7.94 (m, 1 H), 7.86 (s, 1 H), 7.77 (m, 3 H), 7.61 (dd, 2 H, J₁ =7.7 Hz, J₂ =8.1 Hz), 7.12 (s, 1 H), 3.85 (m, 4 H), 3.14 (m, 4 H).

Part C. Preparation of 1-(3-amidinophenyl)-3-trifluoro-methyl-5-((2'-fluoro-4'-(N-morpholino)phenyl)amino-carbonyl)pyrazole bis-trifluoroacetate and 1-(3-carboxamidophenyl)-3-trifluoromethyl-5-((2'-fluoro-4'-(N-morpholino)phenyl)aminocarbonyl)pyrazole.

Standard Pinner-amidine transformation of the 1-(3-cyanophenyl)-3-trifluoromethyl-5-((2'-fluoro-4'-(N-morpholino)phenyl)aminocarbonyl)pyrazole afforded 0.10 g of 1-(3-amidinophenyl)-3-trifluoromethyl-5-[(2'-fluoro-4'-(N-morpholino)phenyl)aminocarbonyl]pyrazole bis-trifluoroacetate. ¹ HNMR(dmso-d6,300 MHz) δ: 10.35 (s, 1 H), 9.40 (bs, 2 H), 9.11 (bs, 2 H), 7.96 (s, 1 H), 7.87 (t,2 H), 7.72 (t, 1 H), 7.67 (s, 1 H), 7.27 (t, 1 H), 6.84-6.71 (m, 2 H), 3.70-3.66 (m, 4 H), 3.09-3.06 (m, 4 H). ESI mass spectrum analysis m/z(relative intensity) 476.5 (M+H, 100). HRMS(CI): Calculated for C22H21N6O2F4 477.166212, found 477.166415. ¹⁹ F NMR (dmso-d6,300 MHz) δ: -61.354, -74.772 and 0.002 g of 1-(3-carboxamidophenyl)-3-trifluoromethyl-5-((2'-fluoro-4'-(N-morpholino)phenyl)aminocarbonyl)pyrazole after HPLC purification. ¹ HNMR(DMSO-d6) δ: 10.31 (s, 1 H), 8.10 (s, 1 H), 7.98-7.94 (m, 2 H), 7.64-7.50 (m, 2 H), 7.33-7.27 (m, 1 H), 6.83-6.70 (m, 2 H), 3.70-3.66 (m, 4 H), 3.09-3.06 (m, 4 H). ESI mass spectrum analysis m/z(relative intensity) 477.5 (M+H, 100). ¹⁹ F NMR (DMSO-d δ: -61.274, -74.363. HRMS(CI): Calculated for C22H20N5O3F4 478.150228, found 478.147507.

EXAMPLE 232 1-(3-aminomethylphenyl)-3-trifluoromethyl-5-((3-trifluoromethyl-4-(N-morpholino)phenyl)aminocarbonyl)pyrazole bis-trifluoroacetate

Part A. Preparation of 3-trifluoromethyl-4-N-morpholinoaniline.

3-Trifluoromethyl-4-N-morpholinonitrobenzene (1.0 g,3.62 mmol) was added to a suspension of palladium on carbon (10%) in 25 mL methanol. The reaction mixture was placed under 1 atmosphere H₂ at ambient temperature for 24 h. Passed reaction mixture through a Celite pad and concentrated filtrate under reduced pressure to give the desired aniline in quantitative yeild. ¹ HNMR(DMSO-d6) δ: 7.20 (d, 1 H, J=7.2 Hz), 6.92 (d, 1 H, J=2.6), 6.81 (dd, 1 H, J₁ =2.9 Hz, J₂ =8.4 Hz), 3.80 (m, 4 H), 3.74 (bs, 2 H), 2.83 (bt, 4 H, J=4.4 Hz), 3.70-3.66 (m, 4 H), 3.09-3.06 (m, 4 H). Ammonia CI mass spectrum analysis m/z(relative intensity) 247 (M+H,100).

Part B. Preparation of 1-(3-cyanophenyl)-3-trifluoromethyl-5-((3'-trifluoromethyl-4'-(N-morpholino)phenyl)aminocarbonyl)pyrazole.

Dimethylaminopyridine(0.25 g,2.01 mmol) was added to a slight suspension of 3-trifluoromethyl-4-N-morpholinoaniline(0.41 g, 1.67 mmol) and N-(3-cyanophenyl)-3-trifluoromethyl-pyrazole-5-carboxylic acid chloride(0.50 g,1.67 mmol) in 20 mL methylene chloride. The reaction mixture was stirred at ambient temperature for 24 h, concentrated under reduced pressure and purified by flash chromatography to give 0.38 g of pure 1-(3-cyanophenyl)-3-trifluoromethyl-5-((3'-trifluoromethyl-4'-(N-morpholino)phenyl)aminocarbonyl)pyrazole. ¹ HNMR(dmso-d6,300 MHz) δ: 7.79 (m, 5 H), 7.62 (dd, 1 H, J₁ =7.7 Hz, J₂ =8.1 Hz), 7.38 (d, 1 H, J=8.4 Hz), 7.15 (s, 1 H), 3.83 (bt, 4 H, J=4.4), 2.91 (bt, 4 H, J=4.4 Hz). Ammonia CI mass spectrum analysis m/z(relative intensity) 510 (M+H, 100). ¹⁹ F NMR (DMSO-d6) δ: -61.033 and -62.854.

Part C. Preparation of 1-(3-amidinophenyl)-3-trifluoromethyl-5-((3'-trifluoromethyl-4'-(N-morpholino)phenyl)aminocarbonyl)pyrazole bis-trifluoroacetate.

The 1-(3-cyanophenyl)-3-trifluoromethyl-5-((3'-trifluoro-methyl-4'-(N-morpholino)phenyl)aminocarbonyl)pyrazole (0.38 g,0.75 mmol) was transformed to the corresponding benzylamine by standard catalytic reduction as described previously to afford 0.19 g of 1-(3-amidinophenyl)-3-trifluoromethyl-5-((3'-trifluoromethyl-4'-(N-morpholino)phenyl)aminocarbonyl)-pyrazole bis-trifluoroacetate after HPLC purification. ¹ HNMR(DMSO-d6) δ: 10.92 (s, 1 H), 7.99 (d, 1 H, J=2.6 Hz), 7.88-7.85 (m, 1 H), 7.68 (s, 1 H), 7.63 (s, 1 H), 7.55-7.49 (m, 4 H), 4.11 (bs, 2 H), 3.67-3.64 (m, 4 H), 2.78 (bt, 4 H, J=4.4 Hz). ESI mass spectrum analysis m/z(relative intensity) 514 (M+H, 100). F NMR (dmso-d6,300 MHz) δ: -59.557, -61.305, and -74.290. HRMS(CI): Calculated for C23H22N502F6: 514.167770 found 514.166332.

EXAMPLE 233 1-(3-aminomethylphenyl)-3-ethyl-5-[(3-fluoro-2'-tert-butylaminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole

Part A. Preparation of ethyl-2,4-dioxohexanoate.

Sodium metal (16.50 g,717.39 mmol) was dissolved in 200 mL ethanol. When the solution had cooled 2-butanone (64.26 mL, 717.39 mmol) was added to the solution. After 0.10 h diethyl oxalate (97.43 mL,717.39 mmol) was added to the reaction mixture. Warmed reaction mixture to 65° C. for 4 h, concentrated under reduced pressure and treated with 200 mL 1.0 M hydrochloric acid solution. Extracted with 200 mL EtOAc and washed organics 2×150 mL water and 2×150 mL brine solution. Dried resulting organics over magnesium sulfate, concentrated under reduced pressure and purified by flash chromatography to give 21.13 g of pure ethyl-2,4-dioxohexanoate. ¹ HNMR(CDCl₃) δ: 14.40 (bs, 1 H), 6.38 (s, 1 H), 4.40-4.32 (m, 2 H), 2.54 (q, 2 H, J=7.7 Hz), 1.41-1.36 (m, 3 H), 1.18 (t, 3 H, J=7.2 Hz).

Part B. Preparation of ethyl(2-methylimino)-4-oxohexanoate.

Ethyl 2,4-dioxohexanoate(21.13 g,0.12 mmol) and methoxylamine hydrochloride(10.26 g,0.12 mmol) were added to a suspension of 3 Å molecular sieves(30 g) in 500 mL anhydrous ethanol. The reaction mixture was stirred mechanically for 24 h. Then the suspension was filtered through a Celite pad and the resulting filtrate was concentrated to give the crude product. Flash chromatography of the crude material gave 6.07 g of pure ethyl (2-methylimino)-4-oxohexanoate. ¹ HNMR(DMSO-d6) δ: 4.33 (q, 2 H, J=7.2 Hz), 4.06 (s, 3 H), 3.71 (s, 3 H), 2.51 (q, 2 H, J=7.2 Hz), 1.35 (t, 3 H, J=7.2 Hz), 1.08 (t, 3 H, J=7.2 Hz). Ammonia CI mass spectrum analysis m/z(relative intensity) 201 (M+H,60), 219 (M+NH4,100).

Part C. Preparation of ethyl(N-(3-cyanophenyl)-3-ethyl)pyrazole-5-carboxylate

To a solution of ethyl(2-methoxyimino)-4-oxohexanoate(1.0 g, 4.98 mmol) in 50 mL glacial acetic acid was added 3-cyano-phenylhydrazine hydrochloride(0.84 g,4.98 mmol). The reaction mixture was warmed to reflux temperature for 4 h, concentrated under reduced pressure and purified by flash chromatography to give 0.98 g of ethyl(N-(3-cyanophenyl)-3-ethyl)pyrazole-5-carboxylate. ¹ HNMR(DMSO-d6) δ: 7.77-7.76 (m, 1 H), 7.72-7.68 (m, 2 H), 7.56 (t, 1 H, J=8.0 Hz), 6.89 (s, 1 H), 4.30-4.23 (m, 2 H), 2.73 (q, 2 H, J=8.0 Hz), 1.33-1.27 (m, 6 H). Ammonia CI mass spectrum analysis m/z(relative intensity) 270 (M+H, 100).

Part D. Preparation of 1-(3-cyanophenyl)-3-ethyl-5-((4-bromo-2-fluorophenyl))aminocarbonyl)pyrazole.

To a solution of 4-bromo-2-fluoroaniline(2.06 g,10.82 mmol) and ethyl (3-cyanophenyl)-3-ethyl)pyrazole-5-carboxylate (0.97 g,3.61 mmol) in 20 mL methylene chloride was added trimethylaluminum (2.OM in hexanes, 5.41 mL,10.82 mmol) in a dropwise fashion over 0.3 h. The reaction mixture was stirred at ambient temperature for 72 h, quenched carefully with 1.OM hydrochloric acid solution, washed 4×50 mL 1.OM hydrochloric acid solution, dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by flash chromatography to afford 0.23 g of 1-(3-cyanophenyl)-3-ethyl-5-[(4-bromo-2-fluorophenyl)]aminocarbonyl)pyrazole. ¹ HNMR(DMSO-d6) δ: 8.17 (t, 1 H, J=8.0 Hz), 7.82 (m, 2 H), 7.71 (m, 2 H), 7.56 (dd, 1 H, J₁ =8.0 Hz, J₂ =7.7 Hz), 7.33 (m, 1 H), 6.72 (s, 1 H), 2.77 (m, 2 H), 1.34 (t, 3 H, J=7.7 Hz). Ammonia CI mass spectrum analysis m/z(relative intensity) 415 (M+H, 100).

Part E. Preparation of 1-(3-cyanophenyl)-3-ethyl-5-[(3-fluoro-2-tertbutylaminosulfonyl-[1,1']-biphen-4-yl)amino-carbonyl]pyrazole.

To a nitrogen purged solution of 1-(3-cyanophenyl)-3-ethyl-5-((4-bromo-2-fluorophenyl))aminocarbonyl)pyrazole(0.23 g, 0.56 mmol), 2-tert-butylaminosulfonylphenylboronic acid(0.17 g, 0.67 mmol) and sodium carbonate(O.12 g,1.12 mmol) in 10 mL ethanol and 20 mL toluene was added catalytic tetrakis-triphenylphosphine palladium. The reaction mixture was heated to 80° C. for 15 h, concentrated under reduced pressure and purified by flash chromatography to afford 0.13 g of 1-(3-aminomethylphenyl)-3-ethyl-5-[(2'-fluoro-2-tertbutylaminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole. ¹ HNMR(DMSO-d6) δ: 8.36 (t, 1 H, J=8.0 Hz), 8.16 (m, 1 H), 7.97 (bd, 1 H, J=3.0 Hz), 7.85 (s, 1 H), 7.77 (d, 1 H, J=8.1 Hz), 7.70 (d, 1 H, J=7.8 Hz), 7.54 (m, 3 H), 7.41 (dd, 1 H, J₁ =1.8 Hz, J₂ =11.7 Hz), 7.25 (m, 2 H) 6.76 (s, 1 H), 3.67 (s, 1 H), 2.79 (q, 2 H, J=8.0 Hz), 1.36 (t, 3 H, J=8.0 Hz), 1.06 (s, 9 H). Ammonia CI mass spectrum analysis m/z(relative intensity) 546 (M+H, 100). ¹⁹ F NMR (dmso-d6,300 MHz) δ: -130.963.

Part F. Preparation of 1-(3-aminomethylphenyl)-3-ethyl-5-[(3-fluoro-(2-tertbutylaminosulfonyl-[1,1']-biphen-4-yl))aminocarbonyl]pyrazole.

Standard transformation of the benzonitrile obtained in part C to the benzylamine via the catalytic reduction followed by treatment with refluxing trifluoroacetic acid converted the 1-(3-cyanophenyl)-3-ethyl-5-[(3-fluoro-2-tertbutylaminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole to 1-(3-aminomethylphenyl)-3-ethyl-5-[(3-fluoro-2-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole trifluoroacetate. The crude product was purified by standard HPLC purification technique. ¹ HNMR(DMSO-d6) δ: 8.01-7.98 (m, 1 H), 7.63-7.56 (m, 4 H), 7.45-7.25 (m, 5 H), 7.16 (d, 1 H, J=8.4 Hz), 6.96 (s, 1 H), 3.95 (s, 2 H), 2.66 (q, 2 H, J=7.7 Hz), 1.24 (t, 3 H, J=7.7 Hz). ESI mass spectrum analysis m/z(relative intensity) 493.9 (M+H,100). HRMS(CI): Calculated for C25H24N5O3FS 493.158390, found 493.156279.

EXAMPLE 234 1-(3-Aminomethylphenyl)-3-ethyl-5-((3-fluoro-2'-metliylsulfonyl-[1,1']-biphen-4-yl))aminocarbonyl)pyrazole trifluoroacetate

Part A. Preparation of 1-(3-cyanophenyl)-3-ethyl)pyrazole-5-carboxylic acid chloride.

To a chilled solution (0° C.) of ethyl 1-(3-cyanophenyl)-3-ethyl)pyrazole-5-carboxylate (7.13 g, 26.51 mmol) in 100 mL water and 150 mL tetrahydrofuran was added lithium hydroxide (1.33 g, 31.81 mmol). The reaction mixture was allowed to warm to ambient temperature overnight and was concentrated under reduced pressure. The resulting aqueous solution was washed 3×100 mL diethylether and acidified with concentrated hydrochloric acid solution to give a white precipitate that was isolated by vacuum filtration. The white solid was place under high vacuum for 24 h and a portion (0.31 g, 1.27 mmol) was treated with oxalyl chloride (0.17 mL, 1.90 mmol) and dimethylformamide (0.1 mL) in 10 mL methylene chloride. After 24 h at ambient temperature the reaction mixture was concentrated and the resulting solid was placed under high vacuum to give the crude 1-(3-cyanophenyl)-3-ethyl)pyrazole-5-carboxylic acid chloride. The crude acid chloride was used without further purification.

Part B. Preparation of 1-(3-cyanophenyl)-3-ethyl-5-((3-fluoro-2'-methylsulfonyl-[1,1']-biphen-4-yl)aminocarbonyl)pyrazole.

To a solution of 2-fluoro-2'-methylsulfonylphenyl)aniline hydrochloride(0.38 g,1.27 mmol) and crude 1-(3-cyanophenyl)-3-ethyl)pyrazole-5-carboxylic acid chloride(1.27 mmol) in 10 mL dichloromethane was added dimethylaminopyridine (0.34 g, 2.79 mmol). The reaction mixture was stirred at ambient temperature for 24 h, concentrated under reduced pressure and purified by flash chromatography to afford 0.23 g of 1-(3-cyanophenyl)-3-ethyl-5-((2'-fluoro-2-methylsulfonyl-[1,1']-biphen-4-yl))aminocarbonyl)pyrazole. ¹ HNMR(DMSO-d6) δ: 10.42 (s, 1 H), 8.06 (dd, 1 H, J₁ =2.0 Hz, J₂ =8.0 Hz), 7.95-7.94 (m, 1 H), 7.85-7.60 (m, 6 H) , 7.42-7.32 (m, 2 H) , 7.20 (dd, 1 H, J₁ =2.0 Hz, J₂ =8.0 Hz), 7.08 (s, 1 H), 2.89 (s, 3 H), 2.67 (q, 2 H, J=7.7 Hz), 1.24 (t, 3 H, J=7.7 Hz). Ammonia CI mass spectrum analysis m/z(relative intensity) 489 (M+H,100).

Part C. Preparation of 1-(3-aminomethylphenyl)-3-ethyl-5-(3-fluoro-2'-methylsulfonyl-[1,1']-biphen-4-yl)aminocarbonyl)pyrazole.

To a suspension of 1-(3-cyanophenyl)-3-ethyl-5-((2'-fluoro-2'-methylsulfonyl-[1,1']-biphen-4-yl)aminocarbonyl)pyrazole (0.103 g,0.211 mmol) and cobalt chloride (0.003 g,0.021 mmol) in 10 mL methanol was added sodium borohydride (0.016 g,0.422 mmol). After 1 H additional sodium borohydride (0.016 g, 0.422 mmol) was added. Let reaction mixture stir for 2 h. Then concentrated reaction mixture under reduced pressure and took up resulting residue in 1.0 hydrochloric acid solution to give a white precipitate. Isolated precipitate by vacuum filtration and purified solid by HPLC to give 0.030 g of pure 1-(3-aminomethylphenyl)-3-ethyl-5-(3-fluoro-2'-methylsulfonyl-[1,1']-biphen-4-yl)aminocarbonyl)pyrazole trifluoroacetate. ¹ HNMR(DMSO-d6) δ: 10.45 (s, 1 H) 8.06 (dd, 1 H, J₁ =2.0 Hz, J₂ =8.0 Hz), 7.77-7.61 (m, 5 H), 7.47-7.31 (m, 4 H), 7.21-7.17 (m, 1 H), 7.01 (s, 1 H), 4.07-4.06 (m, 2 H), 2.90 (s, 3 H), 2.66 (q, 2 H, J=7.7 Hz), 1.24 (t, 3 H, J=7.7 Hz). ESI mass spectrum analysis m/z(relative intensity) 493 (M+H,100). HRMS Calculated for C26H26N4O3FS: 493.170966, found 493.172100.

EXAMPLE 235 1-(3-Aminomethylphenyl)-3-ethyl-5-[(2-fluoro-4-(2-methylsulfonylimidazol-1-yl)phenyl)]aminocarbonyl)pyrazole trifluoroacetate

Part A. Preparation of 4-(2'-methylthioimidazol-1-yl)nitrobenzene.

To a stirred suspension of potassium carbonate(40.07 g, 22.60 mmol) in 175 mL acetone was added 1-(4-nitrophenyl) imidazoline-2-thione(5.0 g,22.60 mmol). Dripped iodomethane (1.44 mL,23.05 mmol) into reaction mixture and heated to reflux temperature for 20 h. Concentrated reaction mixture under reduced pressure and took up resulting solid in 200 mL water. Extracted aqueous three times with ethyl acetate. Combined extracts, dried over magnesium sulfate and concentrated in vacuo to give 5.29 g of crude 4-(2'-methylthioimidazol-1-yl)nitrobenzene. ¹ HNMR(DMSO-d6) δ: 10.45 (s, 1 H) 8.06 (dd, 1 H, J₁ =2.0 Hz, J₂ =8.0 Hz), 8.38-8.33 (m, 2 H), 7.77-7.72 (m, 2 H), 7.61 (d, 1 H, J=1.5 Hz), 7.14 (d, 1 H, J=1.5 Hz), 2.52 (s, 3 H). ESI mass spectrum analysis m/z(relative intensity) 236 (M+H,100).

Part B. Preparation of 4-(2'-methylsulfonylimidazol-1-yl)nitrobenzene.

To a cooled solution (0° C.) of 4-(2'-methylthioimidazol-1-yl)nitrobenzene (1.05 g,4.47 mmol) in 40 mL dichloromethane was added meta-chloroperoxybenzoic acid(1.54 g,8.94 mmol). The reaction mixture was allowed to warm to ambient temperature over 20 H. Washed reaction mixture 3×75 mL 1.0 M sodium hydroxide solution. Dried resulting organics over magnesium sulfate and concentrated under reduced pressure to give 0.98 g of crude 4-(2'-methylsulfonylimidazol-1-yl)nitrobenzene. ¹ HNMR(DMSO-d6) δ: 8.39 (d, 2 H, J=8.7 Hz), 7.73 (d, 2 H, J=8.7 Hz), 7.28-7.23 (m, 2 H), 3.43 (s, 3 H). Ammonia CI mass spectrum analysis m/z(relative intensity) 268 (M+H,100).

Part C. Preparation of 4-(2'-methylsulfonylimidazol-1-yl)aniline.

Standard catalytic reduction of 4-(2'-methylsulfonylimidazol-1-yl)nitrobenzene (0.98 g,3.67 mmol) with palladium on carbon(10%) in methanol gave 0.80 g of 4-(2'-methylsulfonylimidazol-1-yl)aniline.

¹ HNMR (CDCl3) δ: 7.24 (d, 2 H, J=8.7 Hz), 7.15 (dd, 2 H, J₁ =18.3 Hz, J₂ =18.6 Hz), 6.72 (d, 2 H, J=8.7 Hz), 3.30 (s, 3 H). Ammonia CI mass spectrum analysis m/z(relative intensity) 238 (M+H,100).

Part C. Preparation of 1-(3-cyanophenyl)-3-ethyl-5-((2'-fluoro-4'-(2-methylsulfonylimidazol-1-yl)phenyl))aminocarbonyl)pyrazole.

Dimethylaminopyridine (0.42 g,3.48 mmol) was added to a solution of 4-(2'-methylsulfonylimidazol-1-yl)aniline(0.37 g,1.58 mmol) and 1-(3-cyanophenyl)-3-ethyl)pyrazole-5-carboxylic acid chloride (1.58 mmol) in 15 mL dichloromethane. The reaction mixture was stirred at ambient temperature for 15 H, concentrated under reduced pressure and purified by flash chromatography to give 0.37 g of 1-(3-cyanolphenyl)-3-ethyl-5-[(2'-fluoro-4'-(2-methylsulfonylimidazol-1-yl)phenyl)]aminocarbonyl)pyrazole. ESI mass spectrum analysis m/z(relative intensity) 460.9 (M+H, 100), 482.9 (M+Na).

Part D. Preparation of 1-(3-aminomethylphenyl)-3-ethyl-5-[(2'-fluoro-4'-(2-methylsulfonylimidazol-1-yl)phenyl)]aminocarbonyl)pyrazole.

Standard catalytic reduction of 1-(3-cyanophenyl)-3-ethyl-5-[(2'-fluoro-4'-(2-methylsulfonylimidazol-1-yl)phenyl)]aminocarbonyl)pyrazole with palladium on carbon(10%) in methanol gave 0.10 g of 1-(3-aminomethylphenyl)-3-ethyl-5-[(2'-fluoro-4'-(2-methylsulfonylimidazol-1-yl)phenyl)]aminocarbonyl)pyrazole trifluoroacetate after HPLC purification. ¹ HNMR(CDCl₃, 300 MHz) δ: 10.78 (s, 1 H), 7.76 (d, 2 H, J=8.8 Hz), 7.63 (d, 2 H, J=1.1 Hz), 7.49-7.35 (m, 5 H) 7.26 (d, 1 H, J=1.1 Hz), 6.98 (s, 1 H), 4.08 (s, 2 H), 3.35 (s, 3 H), 2.67 (q, 2 H, J=7.7 Hz), 1.24 (t, 3 H, J=7.7 Hz). ESI mass spectrum analysis m/z(relative intensity) 464.9 (M+H,100). HRMS calculated for C23H25N6O3S: 465.170886, found 465.172332.

EXAMPLE 236 1-[(6-(aminomethyl)pyrid-2-yl)]-3-methyl-5-[(2'-anminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole, trifluoroacetic acid salt.

Part A. Preparation of ethyl 1-[pyrid-2-yl]-3-methylpyrazole-5-carboxylate.

To a solution of 2-hydrazinopyridine (0.68 g, 6.24 mmol) in 15 mL of glacial acetic acid was added ethyl 2-methoxyimino-4-oxopentanoate (0.90 g, 4.80 mmol). The resulting mixture was allowed to stir at 100° C. for 2 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was diluted with ethyl acetate, washed with saturated aq sodium carbonate and brine, dried (MgSO₄) and concentrated in vacuo. The residue was purified by flash chromatography (elution with 3:1 hexanes/ethyl acetate) to give 0.4 g (36%) of the title compound. ¹ HNMR(CDCl₃) δ: 8.45 (dd, 1 H), 7.82 (td, 1 H), 7.61 (d, 1 H), 7.29 (dd, 1 H), 6.70 (s, 1 H), 4.25 (q, 2 H), 2.38 (s, 3 H), 1.23 (t, 3 H). Ammonia CI mass spectrum analysis m/z(relative intensity) 232 (M+H, 100).

Part B. Preparation of ethyl 1-[6-cyanopyrid-2-yl]-3-methylpyrazole-5-carboxylate.

To a solution of of ethyl 1-[pyrid-2-yl]-3-methylpyrazole-5-carboxylate (1.4 g, 6.05 mmol) in 10 mL of glacial acetic acid was added 6 mL (large excess) of 30% H₂ O₂. The reaction was stirred at 100° C. for 3 h and then was allowed to cool to room temperature and was poured into saturated aq sodium carbonate. The resulting mixture was extracted with ethyl acetate and the combined organic extracts were washed with brine, dried (MgSO₄) and concentrated in vacuo. The resulting crude N-oxide was dissolved in 20 mL of tetrahydrofuran and then there was added trimethylsilyl cyanide (2.4 mL, 18.2 mmol) followed by dimethylcarbamoyl chloride (1.7 mL, 18.2 mmol). The reaction was allowed to stir at 65° C. for 18 h. The reaction was allowed to cool and was diluted with ethyl acetate, washed with saturated aq sodium bicarbonate and brine, dried (MgSO₄) and concentrated in vacuo. The residue was purified by flash chromatography (elution with 3:1 hexanes/ethyl acetate) to give 0.66 g (43%) of the title compound as a white solid. ¹ HNMR(CDCl₃) δ: 7.98 (m, 2 H), 7.61 (td, 1 H), 6.67 (s, 1 H), 4.38 (q, 2 H), 2.38 (s, 3 H), 1.32 (t, 3 H). Ammonia CI mass spectrum analysis m/z (relative intensity) 257 (M+H, 100).

Part C. Preparation of 1-[(6-cyanopyrid-2-yl)]-3-methyl-5-[(2'-tert-butylaminosulfonyl- [1,1']-biphen-4-yl) aminocarbonyl]pyrazole.

To a solution of (2'-tert-butylaminosulfonyl- [1,1']-biphen-4-yl)amine (0.24 g, 0.78 mmol) in 20 mL of methylene chloride at 25° C. was added trimethylaluminum (1.2 mL of a 2.0 M solution in toluene, 2.34 mmol) dropwise. The resulting solution was allowed to stir until no more gas evolution was observed (˜15 min). To this solution was added ethyl 1-[6- cyanopyrid-2-yl]-3-methylpyrazole-5-carboxylate (0.20 g, 0.78 mmol) as a solution in methylene chloride. The resulting solution was stirred at 40° C. for 3 h and then was cooled to 25° C. and quenched by the addition of saturated aq NH₄ Cl. After diluting with ethyl acetate, the layers were separated and the organic layer was washed with brine, dried (MgSO₄) and concentrated in vacuo. The residue was purified by flash chromatography (elution with 1:1 hexanes/ethyl acetate) to afford 0.15 g (38%) of the title compound as a solid. ¹ HNMR(CDCl₃) δ: 10.63 (s, 1 H), 8.20 (t, 1 H), 8.08 (d, 1 H), 7.98 (m, 2 H), 7.64 (d, 2 H), 7.59 (td, 1 H), 7.51 (td, 1 H), 7.34 (d, 2 H), 7.28 (d, 1 H), 6.80 (s, 1 H), 6.46 (s, 1 H), 2.31 (s, 3 H), 0.97 (s, 9 H). ESI mass spectrum analysis m/z(relative intensity) 515.1 (M+H, 100).

Part D.Preparation of 1-[(6-(aminomethyl)pyrid-2-yl)]-3-methyl-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole, trifluoroacetic acid salt.

To a solution of 1-[(6-cyanopyrid-2-yl)]-3-methyl-5-[(2'-tert-butylaminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole (0.14 g, 0.27 mmol) in 15 mL of absolute ethanol was added 12 N HCl (0.023 mL, 0.27 mmol) and 10% Pd/C catalyst (30 mg). The resulting mixture was stirred under 1 atm of H₂ for 18 h. The mixture was then filtered through a pad of celite and was concentrated in vacuo. The residue was taken up in 3 mL of trifluoroacetic acid and stirred at 80° C. for 20 min. This solution was cooled and concentrated in vacuo. The residue was purified by prep HPLC (C18 reverse phase column, elution with a H₂ O/CH₃ CN gradient with 0.5% TFA) and lyophilized to afford 70 mg (45%) of the title compound as a white powder. ¹ HNMR(DMSO-d6) δ: 10.56 (s, 1 H), 8.18 (broad s, 3 H), 8.02 (m, 2 H), 7.64 (m, 4 H), 7.58 (m, 2 H), 7.45 (d, 1 H), 7.33 (d, 2 H), 7.27 (m, 2 H), 6.84 (s, 1 H), 4.02 (broad q, 2 H), 2.30 (s, 3 H). ESI mass spectrum analysis m/z(relative intensity) 462.9 (M+H, 100).

EXAMPLE 237 1-[(6-(N-hlydroxyamidino)pyrid-2-yl)]-3-methyl-5-[(2'-tert-butylaminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole

Preparation of 1-[(6-(N-hydroxyamidino)pyrid-2-yl)]-3-methyl-5-[(2'-tert-butylaminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole.

To a solution of 1-[(6-cyanopyrid-2-yl)]-3-methyl-5-[(2'-tert-butylaminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole (0.11 g, 0.21 mmol) in 5 mL of absolute ethanol was added hydroxylamine hydrochloride (0.054 g, 0.77 mmol) and sodium carbonate (0.039 g, 0.36 mmol). This mixture was stirred at 80° C. for 1 h and then was allowed to cool. The mixture was diluted with ethyl acetate, washed with brine, dried (MgSO₄) and concentrated in vacuo. The solid residue was triturated with ether to afford 80 mg (68%) of the title compound as a white solid. ¹ HNMR(CDCl₃) δ: 10.79 (s, 1 H), 9.95 (s, 1 H), 8.0 (dd, 1 H), 7.95 (t, 1 H), 7.80 (d, 1 H), 7.68 (m, 3 H), 7.59 (td, 1 H), 7.51 (td, 1 H), 7.35 (m, 3 H), 6.68 (s, 1 H), 6.65 (s, 1 H), 5.43 (broad s, 2 H), 2.31 (s, 3 H), 0.96 (s, 9 H). ESI mass spectrum analysis m/z(relative intensity) 548.1 (M+H, 100).

EXAMPLE 238 1-[(6-amidinopyrid-2-yl)]-3-methyl-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole, trifluoroacetic acid salt

Preparation of 1-[(6-amidinopyrid-2-yl)]-3-methyl-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole, trifluoroacetic acid salt.

To a solution of 1-[(6-cyanopyrid-2-yl)]-3-methyl-5-[(2'-tert-butylaminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole (0.28 g, 0.54 mmol) in 20 mL of absolute ethanol was added triethylamine (0.38 mL, 2.7 mmol). Hydrogen sulfide gas was bubbled slowly through this solution (excess H₂ S was scrubbed through Chlorox bleach) for 20 min.

The flask was stoppered tightly and allowed to stand at room temperature overnight. The solution was concentrated in vacuo. The crude thioamide residue was dissolved in 10 mL of acetone and then there was added 2 mL (large excess) of methyl iodide. The resulting solution was stirred at 60° C. for 2 h and then was cooled and concentrated in vacuo. The residue was dissolved in methanol and then there was added ammonium acetate (1.8 mL of a 1.5 M solution in methanol, 2.7 mmol). The resulting mixture was stirred at 60° C. for 2 h and then was cooled and concentrated in vacuo. The residue was dissolved in trifluoroacetic acid and stirred at 80° C. for 20 min and then was allowed to cool and was concentrated in vacuo. The residue was purified by prep HPLC (C18 reverse phase column, elution with a H₂ O/CH₃ CN gradient with 0.5% TFA) and lyophilized to afford 78 mg (24%) of the title compound as a white powder. ¹ HNMR(d6-DMSO) δ: 10.70 (s, 1 H), 9.36 (broad s, 2 H), 9.04 (broad s, 2 H), 8.31 (t, 1 H), 8.13 (m, 2 H), 8.00 (d, 1 H), 7.63 (d, 2 H), 7.58 (m, 2 H), 7.34 (d, 2 H), 7.28 (d, 1 H), 7.23 (broad s, 2 H), 6.87 (s, 1 H), 2.33 (s, 3 H). ESI mass spectrum analysis m/z(relative intensity) 476.2 (M+H, 100). HRMS: calculated for C₂₃ H₂₂ N₇ O₃ S: 476.150485; Observed: 476.152830.

EXAMPLE 239 1-[6-amidinopyrid-2-yl]-3-methyl-5-[3-fluoro-(2'-methylsulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole, trifluoroacetic acid salt

Part A. Preparation of ethyl 1-[(6-thiocarbonylamino)pyrid-2-yl]-3-methylpyrazole-5-carboxylate.

To a solution of ethyl 1-[6-cyanopyrid-2-yl]-3-methylpyrazole-5-carboxylate in 100 mL of absolute ethanol was added triethylamine (2.7 mL, 19.4 mmol). Hydrogen sulfide gas was slowly bubbled through this solution (excess H₂ S was scrubbed through Chlorox bleach) for 20 min. The flask was stoppered tightly and allowed to stand at room temperature overnight. The solution was concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with 10% aq HCl and brine, dried (MgSO₄) and concentrated in vacuo to afford 1.1 g (97%) of the title compound which was sufficiently pure to be used without purification. ¹ HNMR(CDCl₃) δ: 9.01 (broad s, 1 H), 8.55 (dd, 1 H), 7.92 (t, 1 H), 7.82 (dd, 1 H), 7.58 (broad s, 1 H), 6.66 (s, 1 H), 4.22 (q, 2 H), 2.33 (s, 3 H), 1.18 (t, 3 H). ESI (-ve) mass spectrum analysis m/z(relative intensity) 288.9 (M-H, 100).

Part B. Preparation of 1-[(6-thiocarbonylamino)pyrid-2-yl]-3-methyl-5-[(1-bromo-3-fluorophenyl-4-yl)aminocarbonyl]pyrazole.

To a solution of 4-bromo-2-fluoroaniline (2.17 g, 11.4 mmol) in 150 mL of methylene chloride was added trimethylaluminum (11.4 mL of a 2 M solution in toluene, 22.8 mmol) dropwise. This solution was stirred until gas evolution ceased (15-20 min) and then there was added ethyl 1-[(6-thiocarbonylamino)pyrid-2-yl]-3-methylpyrazole-5-carboxylate (1.1 g, 3.8 mmol) in methylene chloride. The resulting solution was allowed to stir at reflux for 18 h and then it was cooled and quenched by dropwise addition of saturated aq ammonium chloride. The mixture was diluted with ethyl acetate, the layers were separated, the organic layer was washed with water and brine, dried (MgSO₄) and concentrated in vacuo. The solid residue was purified by trituration with ether and the remaining solid was dried in vacuo to afford 1.26 g (76%) of the title compound. ¹ HNMR(d6-DMSO) δ: 10.62 (broad s, 1 H), 10.20 (broad s, 1 H), 8.84 (broad s, 1 H), 8.33 (dd, 1 H), 8.12 (t, 1 H), 7.98 (d, 1 H), 7.72 (t, 1 H), 7.58 (dd, 1 H), 7.39 (d, 1 H), 6.75 (s, 1 H), 2.30 (s, 3 H) ppm.

Part C. Preparation of 1-[(6-(N-tert-butyloxycarbonyl)aminoiminomethyl)pyrid-2-yl]-3-methyl-5-[(1-bromo-3-fluorophenyl-4-yl)aminocarbonyl]pyrazole.

To a solution of 1-[(6-thiocarbonylamino)pyrid-2-yl]-3-methyl-5-[(1-bromo-3-fluorophenyl-4-yl)aminocarbonyl]pyrazole (1.09 g, 2.51 mmol) in 100 mL of acetone was added 12 mL (large excess) of methyl iodide. The resulting solution was stirred at 60° C. for 2 h and then was cooled and concentrated in vacuo. The residue was dissolved in methanol and then there was added ammonium acetate (8.3 mL of a 1.5 M solution in methanol, 12.5 mmol). The resulting mixture was stirred at 60° C. for 2 h and then was cooled and concentrated in vacuo to afford 1.0 g of the crude amidine. To 0.5 g (1.2 mmol) of this residue in 10 mL of pyridine was added di-tert-butyl dicarbonate (0.52 g, 2.4 mmol) and 4-dimethylaminopyridine (0.29 g, 2.4 mmol). This mixture was allowed to stir at room temperature for 18 h and then was concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with water, 10% aq HCl and brine, dried (MgSO₄) and concentrated in vacuo. The residue was purified by flash chromatography (elution with 1:1 hexanes/ethyl acetate) to afford 0.15 g (24%) of the title compound. ¹ HNMR(CDCl₃) δ: 9.08 (broad s, 1 H), 8.22 (m, 3 H), 7.95 (d, 1 H), 7.85 (t, 1 H), 7.25 (m, 2 H), 6.53 (s, 1 H), 2.33 (s, 3 H), 1.49 (s, 9 H) ppm. ESI mass spectrum analysis m/z 516.9/518.9 (M+H)+.

Part D. Preparation of 1-[(6-(N-tert-butyloxycarbonyl)aminoiminomethyl)pyrid-2-yl]-3-methyl-5-[3-fluoro-(2'-thiomethoxy-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole.

To a solution of 1-[(6-(N-tert-butyloxycarbonyl)aminoiminomethyl)pyrid-2-yl]-3-methyl-5-[(1-bromo-3-fluorophenyl-4-yl)aminocarbonyl]pyrazole (0.15 g, 0.29 mmol) in 15 mL of benzene was added 2-thiomethoxyphenyl boronic acid (0.07 g, 0.42 mmol), tetrabutylammonium bromide (0.01 g, 0.03 mmol), sodium carbonate (0.09 g, 0.85 mmol) and 0.80 mL of water. This mixture was degassed with a stream of nitrogen and then tetrakis triphenylphosphine palladium (0.06 g, 0.05 mmol) was added. The mixture was stirred at 80° C. for 24 h. The reaction was allowed to cool and then was diluted with ethyl acetate, washed with saturated aq sodium bicarbonate and brine, dried (MgSO₄), filtered through celite and concentrated in vacuo to afford 0.157 g (95%) of the title compound. This material was sufficiently pure to be used without purification. ¹ HNMR(CDCl₃) δ: 8.40 (t, 1 H), 8.02 (broad s, 2 H), 7.60-7.20 (m, 10 H), 6.56 (s, 1 H), 2.34 (s, 3 H), 2.33 (s, 3 H), 1.46 (s, 9 H) ppm. ESI mass spectrum analysis m/z(relative intensity) 560.9 (M+H, 100).

Part E. Preparation of 1-[6-amidinopyrid-2-yl]-3-methyl-5-[3-fluoro-(2'-methylsulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole, trifluoroacetic acid salt.

To a solution of 1-[(6-(N-tert-butyloxycarbonyl)aminoiminomethyl)pyrid-2-yl]-3-methyl-5-[3-fluoro-(2'-thiomethoxy-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole (0.157 g, 0.28 mmol) in 20 mL of methylene chloride was added 3-chloroperoxybenzoic acid (0.17 g, 0.99 mmol). The resulting mixture was stirred at room temperature for 24 h and then was diluted with ethyl acetate, washed with saturated aq sodium metabisulfite, saturated aq sodium bicarbonate and brine, dried (MgSO₄) and concentrated in vacuo. The residue was dissolved in 5 mL of trifluoroacetic acid and stirred at 80° C. for 20 min. The reaction was cooled and concentrated in vacuo. The residue was purified by prep HPLC (C18 reverse phase column, elution with a H₂ O/CH₃ CN gradient with 0.5% TFA) and lyophilized to afford 80 mg (47%) of the title compound as a white powder. ¹ HNMR(d6-DMSO) δ: 10.52 (s, 1 H), 9.42 (broad s, 2 H), 9.08 (broad s, 2 H), 8.31 (t, 1 H), 8.12 (m, 3 H), 7.78-7.73 (m, 3 H), 7.42 (d, 1 H), 7.32 (d, 1 H), 7.20 (d, 1 H), 6.89 (s, 1 H), 2.89 (s, 3 H), 2.33 (s, 3 H) ppm. ESI mass spectrum analysis m/z(relative intensity) 493.9 (M+H, 100).

EXAMPLE 240 1-(3-aminomethylphenyl)-3-methyl-5-((2-methoxy-4-(N-morpholino)phenyl) aminocarbonyl)pyrazole trifluoroacetate

Part A: Preparation of 1-(3-N-(benzyloxycarbonyl)aminophenyl)-3-methyl-5-((2-methoxy-4-(N-morpholino)phenyl)aminocarbonyl)pyrazole.

To a solution of 1-(3-N-(benzyloxycarbonyl)aminophenyl)-3-methyl-pyrazole-5-carboxylic acid (183 mg, 0.5 mmol) in DMF (10 mL) was added PyBrop (bromo-tris-pyrrolidino-phosphonium hexafluorophosphate, 280 mg, 0.6 mmol) and the resulting solution was stirred at room temperature for 10 min. N,N-diisopropylethylamine (1 mL) was added and stirred for additional 10 min. To this solution was then added 2-methoxy-4-N-morpholine-aniline (125 mg, 0.6 mmol) and the resulting mixture was stirred at 60° C. for 3 hours. After the mixture was cooled to room temperature, to it was added DOWEX (50WX8-100 ion-exchange resin, 0.5 g) and stirred for additional 0.5 h. The mixture was filtered and the residue was washed with EtOAc (50 mL). The filtrate was washed with brine (5×10 mL), dried over MgSO₄, and purified by column chromatography with EtOAc to give the product (261 mg, 95%). ¹ HNMR(CDCl₃) δ: 7.42-7.31 (m, 10 H), 7.03 (s, 1 H), 6.94 (d, J 8.8 Hz, 1 H), 6.50 (d, J=2.6 Hz, 1 H), 6.42 (dd, J=8.4 Hz, J=2.6 Hz, 1 H), 4.70 (s, 1 H), 4.41 (d, J=3.9 Hz, 2 H), 3.84 (t, J=4.8 Hz, 4 H), 3.78 (s, 3 H), 3.09 (t, J=4.8 Hz, 4 H), 2.35 (s, 3 H) ppm. ESI mass spectrum analysis m/z(relative intensity) 556 (M+H, 100).

Part B: Preparation of 1-(3-aminophenyl)-3-methyl-5-((2-methoxy-4-(N-morpholino)phenyl)aminocarbonyl)pyrazole trifluoroacetate.

To 1-(3-N-(benzyloxycarbonyl)aminophenyl)-3-methyl-5-((2-methoxy-4-(N-morpholino)phenyl)aminocarbonyl)pyrazole (100 mg, 0.18 mmol) was added trifluoroacetic acid (5 mL) and the resulting solution was refluxed for 4 hours. The solution was concentrated and purified on TLC plate with ethyl acetate to a viscous liquid (60 mg, 80%). ¹ HNMR(CD₃ OD) δ: 7.58 (s, 1 H), 7.53-7.48 (m, 3 H), 7.06 (s, 1 H), 6.91 (d, J=8.4 Hz, 1 H), 6.63 (d, J=2.6 Hz, 1 H), 6.47 (dd, J=8.8 Hz, J=2.6 Hz, 1 H), 4.15 (s, 2 H), 3.79 (t, J=4.8 Hz, 4 H), 3.76 (s, 3 H), 3.09 (t, J=4.8 Hz, 4 H), 2.35 (s, 3 H) ppm. ESI mass spectrum analysis m/z(relative intensity) 422 (M+H, 100).

EXAMPLE 241 1-(3-aminomethylphenyl)-3-methyl-5-[4'-(3"-methyl-5"n-oxo-3"-pyrazolin-2"-yl)-phenyl)aminocarbonyl]pyrazole trifluoroacetate

Part A: Preparation of 1-(3-N-(benzyloxycarbonyl)aminophenyl)-3-methyl-5-((4'-(3"-methyl-5"-oxo-3"-pyrazolin-2"-yl)-phenyl)aminocarbonyl)-pyrazole.

To a solution of 1-(3-N-(benzyloxycarbonyl)aminophenyl)-3-methyl-pyrazole-5-carboxylic acid (150 mg, 0.41 mmol) in DMF (5 mL) was added PyBrop (bromo-tris-pyrrolidino-phosphonium hexafluorophosphate, 233 mg, 0.5 mmol) and the resulting solution was stirred at room temperature for 10 min. To this solution was added N,N-dimethylpyridine (70 mg, 0.57 mmol) and stirred for an additional 10 min. 2-(4-aminophenyl)-3-methyl-3-pyrazolin-5-one (125 mg, 0.6 mmol) was added and the resulting mixture was stirred at 60° C. for 24 hours. The mixture was diluted with EtOAc (100 mL), washed with 1 N HCl (10 mL) and brine (5×10 mL), dried over MgSO₄, and purified by column chromatography with EtOAc to afford the product (260 mg). ESI mass spectrum analysis m/z(relative intensity) 537.2 (M+1, 100).

Part B: Preparation of 1-(3-aminophenyl)-3-methyl-5-((2'-methoxy-4'-(N-morpholino)phenyl)aminocarbonyl)pyrazole trifluoroacetate.

To 1-(3-N-(benzyloxycarbonyl)aminophenyl)-3-methyl-5-((4'-(3"-methyl-5"-oxo-3"-pyrazolin-2"-yl)-phenyl)aminocarbonyl)-pyrazole (260 mg) was added trifluoroacetic acid (5 mL) and the resulting solution was refluxed for 2 hours. The solution was concentrated and purified on TLC plate with ethyl acetate to a viscous liquid (120 mg, 74.6% for two steps). ¹ HNMR(CD₃ OD) δ: 7.69 (d, J=8.8 Hz, 2 H), 7.55 (7.55 (bs, 1 H), 7.52-7.46 (m, 3 H), 7.35 (d, J=8.8 Hz, 2 H), 6.87 (s, 1 H), 5.57 (s, 1 H), 4.14 (s, 2 H), 2.35 (s, 3 H), 2.21 9 (s, 3 H) ppm. ESI mass spectrum analysis m/z(relative intensity) 403.1 (M+H, 100).

EXAMPLE 242 1-[3-(aminomethyl)phenyl]-5-[(2'-methylsulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-(methylthio)pyrazole, trifluoroacetic acid salt

Part A: Preparation of 1,1-di(methylthio)ethylene.

In a 2 L flask fitted with mechanical stirrer, condenser, under argon, methyl magnesium bromide (3.0 M in Et₂ O, 84 mL, 252 mmol) was diluted to 1.0 M in THF (168 mL), keeping the pot temperature below 40° C. Carbon disulfide (22.6 mL, 376 mmol) in THF (23 mL) was added over 30 min., and the reaction was maintained at 40° C. for 135 min. Heat was removed and the reaction was cooled to -72° C. Lithium diisopropylamide (2.0 M in heptane, THF, and ethylbenzene, 126 mL, 252 mmol) was added over 35 min., keeping the internal temperature below -60° C. The resulting thick, dark orange-red paste was maintained near -60° C. for 160 min. Dimethyl sulfate (48 mL, 504 mmol) was added over 45 min., and the reaction was allowed to warm to room temperature over 70 min. The mechanical stirrer was turned off, and the reaction stood at room temperature for 17 h. The resulting mixture was diluted with Et₂ O (300 mL) and poured into aq. sodium bicarbonate (20%, 500 mL). An argon atmosphere was maintained for all manipulations. The layers were separated, and the organics were extracted with aq. sodium bicarbonate (25%, 200 mL), dried over MgSO₄, filtered, and concentrated to about 100 mL. The resulting oil was distilled under vacuum (70° C. head temperature, 10 Torr) to yield 25.37 g product contaminated with ethylbenzene, for an estimated yield of pure product (15.59 g, 52%). ¹ HNMR(CDCl₃) δ: 5.24 (s, 2 H), 2.36 (s, 6 H) ppm.

Part B: Preparation of methyl 4,4-di(methylthio)-2-oxo-but-3-enoate.

A solution of 1,1'-di(methylthio)ethylene (19.73 g containing 9.95 g of compound, 83 mmol) in Et₂ O (125 mL) was cooled to -60° C. under argon. Oxalyl chloride (5.6 mL, 64 mmol) was added over 3 min., allowing the internal temperature to reach -55° C. The reaction was warmed to -15° C. over 20 min., and dry methanol (20 mL, 494 mmol) was added over 2 min. The reaction continued to warm and stir at room temperature for 2 h. The resulting mixture was diluted with Et₂ O and filtered under argon to yield a yellow solid (8.28 g, 63%). ¹ HNMR(CDCl₃) δ: 6.84 (s, 1 H), 3.87 (s, 3 H), 2.57 (s, 3 H), 2.55 (s, 3 H) ppm.

Part C: Preparation of methyl 1-(3-cyanophenyl)-3-(methylthio)pyrazole-5-carboxylate.

A mixture of methyl 4,4-di(methylthio)-2-oxo-but-3-enoate (2.0 g, 9.7 mmol), triethylamine (1.5 mL, 10.7 mmol), and m-cyanophenylhydrazine hydrochloride (1.81 g, 10.7 mmol) were combined in dry methanol (20 mL) and heated at reflux for 47 h. The reaction was evaporated and chromatographed on silica gel (CH₂ Cl₂ followed by 40% EtOAc/hexanes) to yield a partially purified intermediate (1.91 g), which was redissolved in acetonitrile (85 mL) and refluxed 23 h. The crude reaction mixture was chromatographed on silica gel in CH₂ Cl₂ to yield desired pyrazole (780 mg, 29%). ¹ HNMR(CDCl₃) δ: 7.78 (s, 1 H), 7.70 (m, 2 H), 7.57 (m, 1 H), 6.95 (s, 1 H), 3.83 (s, 3 H), 2.57 (s, 3 H) ppm.

Part D: Preparation of methyl 1-[3-(aminomethyl)phenyl]-3-(methylthio)pyrazole-5-carboxylate.

To a solution of methyl 1-(3-cyanophenyl)-3-(methylthio)pyrazole-5-carboxylate (777 mg, 2.8 mmol) in dry DMF (50 mL), CoCl₂ (39 mg, 0.30 mmol) and NaBH₄ (158 mg, 4.2 mmol) were added. The initial solution was emerald green, then turned dark black. After stirring for 2 h., additional NaBH₄ (145 mg, 3.8 mmol) was added. After another 3 h., additional CoCl₂ (330 mg, 2.5 mmol) was added. The reaction continued stirring at room temperature for 17 h. Methanol (10 mL) was added and stirred 40 min. to quench the reaction. The reaction was concentrated to 30 mL and chromatographed on silica gel (0%-100% EtOAc/hexanes followed by 10-30% MeOH/CHCl₃) to yield the desired product (198 mg, 25%). ¹ HNMR(CDCl₃) δ: 7.41 (m, 3 H), 7.30 (d, 1 H, J=7.3), 6.90 (s, 1 H), 4.02 (bs., 1 H), 3.78 (s, 3 H), 3.49 (s, 2 H), 2.54 (s, 3 H) ppm.

Part E: Preparation of methyl 1-[3-(t-butoxycarbonylaminomethyl)phenyl]-3-(methylthio)pyrazole-5-carboxylate.

Di-t-butyl dicarbonate (184 mg, 0.84 mmol) was added to a suspension of methyl 1-[3-(aminomethyl)phenyl]-3-(methylthio)pyrazole-5-carboxylate (195 mg, 0.70 mmol) in dry THF (8 mL). After stirring 3 h., additional THF (5 mL) was added to aid solubility. The reaction was stirred an additional 16 h., and additional di-t-butyl dicarbonate (54 mg, 0.25 mmol) was added. After another 5 h., triethylamine (100 μL, 0.72 mmol) was added and stirred 2 h. The reaction was diluted with EtOAc and extracted twice with H₂ O. The aqueous were combined and extracted with EtOAc. The organics were combined, dried over Na₂ SO₄, filtered, evaporated, and chromatographed on silica gel (30% EtOAc) to yield the desired product (228 mg, 86%). ¹ HNMR(CDCl₃) δ: 7.37 (m, 4 H)., 6.91 (s, 1 H), 4.87 (bs, 1 H), 4.38 (d, 2 H, J=5.8), 3.79 (s, 3 H), 2.56 (s, 3 H), 1.46 (s, 9 H) ppm.

Part F: Preparation of 1-[3-(t-butoxycarbonylaminomethyl)phenyl]-3-(methylthio)pyrazole-5-carboxylic acid.

To a solution of methyl 1-[3-(t-butoxycarbonylaminomethyl)phenyl]-3-(methylthio)pyrazole-5-carboxylate (50 mg, 0.13 mmol) in THF (2 mL) was added aq. LiOH (1.0 M, 160 μL, 0.16 mmol). The resulting solution was stirred for 19 h. Additional LiOH (30 μL, 0.03 mmol) was added and stirred for 3 h. The reaction was partitioned between H₂ O and Et₂ O/EtOAc. The aqueous extracts were neutralized with HCl (0.1 M, 1.0 mL) and ice. This aqueous solution was extracted once with Et₂ O/EtOAc. Additional HCl (0.1 M, 0.5 mL) was added and further extracted with Et₂ O/EtOAc. A final pH of 3.5 was reached with additional HCl (0.1 M, 0.4 mL). This was extracted again with EtOAc. The organic extracts after acidification were combined, dried over MgSO₄, filtered, and evaporated to yield the desired product (54 mg, 100%). ¹ HNMR(CDCl₃) δ: 7.33 (m, 4 H), 6.97 (s, 1 H), 4.35 (bd, 2 H, J=4.4 ), 4.27 (bs, 1 H), 2.55 (s, 3 H), 1.45 (s, 9 H) ppm.

Part G: Preparation of 1-[3-(t-butoxycarbonylaminomethyl)phenyl]-5-[(2'-methylsulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-(methylthio)pyrazole.

DMF (3 or 4 drops) was added to a mixture of 1-[3-(t-butoxycarbonylaminomethyl)phenyl]-3-(methylthio)pyrazole-5-carboxylic acid (94 mg, 0.26 mmol) and oxalyl chloride (35 μL, 0.40 mmol) in dry CH₂ Cl₂ (3 mL). The resulting solution was stirred for 55 min. and evaporated. After a few min. under high vacuum, the compound was redissolved in CH₂ Cl₂ (3 mL), and 4-amino-2'-methylsulfonyl-[1,1']-biphenyl hydrochloride (85 mg, 0.30 mmol) and 4-dimethylaminopyridine (85 mg, 0.70 mmol) were added and stirred 20 h. The reaction was diluted with H₂ O and extracted twice with EtOAc. The combined organics were extracted with aq. NaHCO₃ followed by aq. HCl (0.1 M, cooled with ice). Solid NaCl was added to aid separation. The organic layer was removed, and the aqueous solution was extracted an additional 2 times with EtOAc. The organic extracts were combined, dried over Na₂ SO₄, filtered, and evaporated. The crude product was chromatographed on silica gel (50% EtOAc/hexanes ) to yield the desired product (65 mg, 43%). ESI mass spectrum analysis m/z=615 (M+Na)+.

Part H: Preparation of 1-[3-(aminomethyl)phenyl]-5-[(2'-methylsulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-(methylthio)pyrazole, trifluoroacetic acid salt.

1-[3-(t-Butoxycarbonylaminomethyl)phenyl]-5-[(2'-methylsulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-(methylthio)pyrazole (65 mg, 0.11 mmol) was dissolved in CH₂ Cl₂ (3 mL) and TFA (1 mL) and stirred 17 h. The reaction was evaporated and purified by prep. HPLC (10-90% MeCN/H₂ O/0.5% TFA) to yield the desired product (37 mg, 55%). ¹ HNMR(DMSO) δ: 10.78 (s, 1 H), 8.21 (bs, 2 H), 8.08 (d, 1 H, J=7.7), 7.70 (m, 5 H), 7.45 (m, 6 H), 7.16 (s, 1 H), 4.13 (bd, 2 H, J=4.8), 2.84 (s, 3 H), 2.57 (s, 3 H) ppm. ESI mass spectrum analysis m/z=493 (M+H, 100).

EXAMPLE 243 1-(3-aminomethyl-4-fluorophenyl)-3-trifluoromethyl-5-[(3-fluoro-2'-methylsulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-pyrazole, trifluoroacetic acid salt

Part A: Preparation of 1-(3-cyano-4-fluorophenyl)-3-trifluoromethyl-5-methyl pyrazole.

To a mixture of 3-cyano-4-fluorophenylhydrazine tin chloride (10 g, 26.6 mmol) in acetic acid(150 mL) was added 1,1,1-trifluoro-2,4-penpanedione (4.09 g, 26.6 mmol). The reaction mixture was brought to reflux overnight. Acetic acid was removed on rotary evaporator under reduced pressure. Residue was partitioned between ethyl acetate (200 mL) and water (150 mL). Organic phase was separated and washed with water (3×100 mL), dried over sodium sulfate; filtered, concentrated and subjected to silica-gel flash chromatography(ethyl acetate:hexane, 1:10) to afford 1-(3-cyano-4-fluorophenyl)-3-trifluoromethyl-5-methyl pyrazole(4.0 g). CI mass spectrum m/z (rel. intensity) 270 (M+H, 100).

Part B: Preparation of 1-(3-cyano-4-fluorophenyl)-3-trifluoromethyl-5-bromomethyl pyrazole.

To a solution of 1-(3-cyano-4-fluorophenyl)-3-trifluoromethyl-5-methyl pyrazole(4.0 g, 14.87 mmol) in carbon tetrachloride(50 mL) was added NBS(2.65 g, 14.87 mmol) and benzoyl peroxide(0.36 g, 1.48 mmol). The reaction mixture was brought to reflux overnight. Solvent was removed on rotary evaporator under reduced pressure. Residue was partitioned between ethyl acetate(80 mL) and sodium bicarbonate(sat. 80 mL). Organic phase was separated and washed with water(60 mL); dried over sodium sulfate; filtered, concentrated and subjected to silica-gel flash chromatography (ethyl acetate : hexane, 1:10) to afford 1-(3-cyano-4-fluorophenyl)-3-trifluoromethyl-5-bromomethyl pyrazole(2.5 g). CI mass spectrum m/z (rel. intensity) 348 (M+H, 100).

Part C: Preparation of 1-(3-cyano-4-fluorophenyl)-3-trifluoromethyl-5-hydroxymethyl pyrazole.

To a solution of 1-(3-cyano-4-fluorophenyl)-3-trifluoromethyl-5-bromomethyl pyrazole(2.5 g, 7.18 mmol) in DMSO (40 mL) was added copper(I) oxide(2.16 g, 15.08 mmol) and water (12 mL). The reaction mixture was stirred at 60° C. for 2 hours then cooled to RT and stirred at RT overnight. The next day, the mixture was filtered through celite, filter pad was washed with ethyl acetate(20 mL); the filtrate was partitioned between ethyl acetate(50 mL) and water(50 mL); organic phase was separated and washed with water(3×30 mL); dried over sodium sulfate; filtered, concentrated, flash chromatography (ethyl acetate : hexane, 1:6) to afford 1-(3-cyano-4-fluorophenyl)-3-trifluoromethyl-5-hydroxymethyl pyrazole(1.7 g). CI mass spectrum m/z (rel. intensity) 286 (M+H, 100).

Part D: Preparation of 1-(3-cyano-4-fluorophenyl)-3-trifluoromethyl-5-hydroxycarbonylmethyl pyrazole.

To a solution of 1-(3-cyano-4-fluorophenyl)-3-trifluoromethyl-5-hydroxymethyl pyrazole(1.5 g, 5.26 mmol) in acetonitrile(30 mL) was added NaIO₄ (2.65 g, 11.05 mmol), catalytic amount of RuCl₃ and water(30 mL) at 0° C. The reaction mixture was stirred at 0° C. to RT overnight. Acetonitrile was removed on rotary evaporator under reduced pressure. The residue was partitioned between athylacetate(60 mL) and HCl(10%, 25 mL). Organic phase was separated and dried over sodium sulfate, filtered and concentrated to give 1-(3-cyano-4-fluorophenyl)-3-trifluoromethyl-5-hydroxycarbonylmethyl pyrazole(1.4 g). ESI mass spectrum m/z (rel. intensity) 298 (M-H, 100).

Part E: 1-(3-cyano-4-fluorophenyl)-3-trifluoromethyl-5-[(2'-methylsulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-pyrazole.

To a solution of 1-(3-cyano-4-fluorophenyl)-3-trifluoromethyl-5-hydroxycarbonylmethyl pyrazole(0.20 g, 0.67 mmol) in methylene chloride(20 mL) was added ClCOCOCl(0.84 g, 6.7 mmol) and a drop of DMF. The reaction mixture was stirred at RT overnight. Methylene chloride and excess ClCOCOCl was removed on rotary evaporator. The residue was redissolved in methylene chloride(20 mL) and to the solution was added 2'-methylsulfonyl-[1,1']-3-fluoro-4-amino-biphenyl (0.20 g, 0.67 mmol) and DMAP (0.25 g, 2.01 mmol). The mixture was stirred at RT overnight. The next day, mehtylene chloride was removed on rotary evaporator under reduced pressure. The residue was partitioned between ethyl acetate(30 mL) and Hcl(10%, 20 mL). Organic phase was separated and washed with water(2×20 mL), dried over sodium sulfate, filtered and concentrated to leave 1-(3-cyano-4-fluorophenyl)-3-trifluoromethyl-5-[(2'-methylsulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-pyrazole(0.32 g). ESI mass spectrum m/z (rel. intensity) 569 (M+Na, 100).

Part F 1-(3-aminomethyl-4-fluorophenyl)-3-trifluoromethyl-5-[(3-fluoro-2'-methylsulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-pyrazole Trifluoroacetic acid salt.

To a solution of 1-(3-cyano-4-fluorophenyl)-3-trifluoromethyl-5-[(3-fluoro-2'-methylsulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-pyrazole(50 mg) in ethanol(20 mL) was added palladium(10% on activated carbon, 40 mg). The mixture was hydrogenated at 45 psi overnight. The next day, the reaction mixture was filtered through celite, filtrate was concentrated and the residue was purified on HPLC(RP gradient) to give 1-(3-aminomethyl-4-fluorophenyl)-3-trifluoromethyl-5-[(2'-methylsulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-pyrazole(40 mg) as Trifluoroacetic acid salt. ESI mass spectrum z (rel. intensity) 551 (M+H, 100).

EXAMPLE 244 Ethyl 1-[3-(aminomethyl)-phenyl]-5-[3-fluoro-2'-methylsulfonyl-[1,1']-biphen-4-yl)aminocarbonyllpyrazole-3-carboxylate, trifluoroacetic acid salt.

Part A. Preparation of ethyl 4-(2-furyl)-2,4-dioxobutanoate.

To a solution of sodium ethoxide (75 mL of a 21% solution in ethanol, 0.20 mol) in 300 mL of ethanol was added a mixture of 2-acetylfuran (20.0 g, 0.18 mol) and diethyloxalate (26.5 g, 0.18 mol) in 200 mL of tetrahydrofuran over 30 min. The resulting mixture was allowed to stir at room temperature for 18 h. The reaction mixture was filtered and the solids were washed with ether. The solids were dissolved in water and acidified with 10% HCl. The aqueous was extracted with ethyl acetate and the ethyl acetate layer was washed with brine, dried (MgSO₄) and concentrated in vacuo to afford 21.9 g (57%) of the title compound. ¹ HNMR(CDCl₃) δ: 7.68 (d, 1 H), 7.35 (d, 1 H), 6.93 (s, 1 H), 6.62 (dd, 1 H), 4.39 (q, 2 H), 1.40 (t, 3 H) ppm.

Part B. Preparation of ethyl 1-[(3-cyano)phenyl]-5-[fur-2-yl]pyrazole-3-carboxylate.

To a solution of ethyl 4-(2-furyl)-2,4-dioxobutanoate (3.00 g, 14.3 mmol) in 50 mL of absolute ethanol was added 3-hydrazinobenzonitrile (2.09 g, 15.7 mmol) and p-toluenesulfonic acid (2.45 g, 14.3 mmol). This mixture was stirred at 80° C. for 2 h. The reaction was concentrated in vacuo and the residue was taken up in ethyl acetate, filtered through a pad of silica gel and concentrated in vacuo. The residue was recrystallized from hexanes to afford 3.1 g (70%) of the title compound. ¹ HNMR(CDCl₃) δ: 7.80-7.70 (m, 4 H), 7.58 (t, 1 H), 7.42 (d, 1 H), 7.16 (s, 1 H), 6.42 (dd, 1 H), 6.24 (d, 1 H), 4.45 (q, 2 H), 1.42 (t, 3 H) ppm. ESI mass spectrum analysis m/z 308.1 (M+H)+.

Part C. Preparation of ethyl 1-[(3-cyano)phenyl]-5-[carboxy]pyrazole-3-carboxylate.

To a solution of ethyl 1-[(3-cyano)phenyl]-5-[fur-2-yl]pyrazole-3-carboxylate (1.00 g, 3.25 mmol) in 50 mL of a 2:3:2 mixture of acetonitrile/water/carbon tetrachloride was added sodium periodate (3.13 g, 14.64 mmol) and ruthenium trichloride hydrate (0.015 g, 0.071 mmol). The mixture was stirred at room temperature for 1 h and then was concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with brine, dried (MgSO₄) and concentrated in vacuo. The residue was triturated with ether to afford 0.9 g (96%) of the title compound. ¹ HNMR(DMSO-d₆) δ: 8.15 (m, 1 H), 7.99 (m, 1 H), 7.91 (m, 1 H), 7.87 (t, 1 H), 7.38 (s, 1 H), 4.30 (q, 2 H), 1.27 (t, 3 H) ppm. ESI mass spectrum analysis: (AP+) m/z 286.1 (M+H)+.

Part D. Preparation of ethyl 1-(3-cyanophenyl)-5-[(3-fluoro-2'-methylsulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole-3-carboxylate.

To a solution ethyl 1-[(3-cyano)phenyl]-5-[carboxy]pyrazole-3-carboxylate ( 0.49 g, 1.72 mmol) in 10 mL of benzene was added oxalyl chloride (0.22 mL, 2.58 mmol) and about 3 drops of dimethylformamide. This solution was allowed to stir at room temperature for 6 h and then was concentrated in vacuo. The residue was dissolved in methylene chloride and then there was added (3-fluoro-2'-methylsulfonyl-[1,1']-biphen-4-yl)amine (0.52 g, 1.72 mmol) and 4-dimethylaminopyridine (0.63 g, 5.17 mmol). The resulting mixture was stirred at room temperature for 18 h. The reaction was diluted with ethyl acetate, washed with 10% aq HCl, saturated aq sodium bicarbonate and brine, dried (MgSO₄) and concentrated in vacuo. The residue was purified by flash chromatography (elution with 2:1 hexanes/ethyl acetate) to afford the 0.70 g (76%) of the title compound. ¹ HNMR(CDCl₃) δ: 8.32 (t, 1 H), 8.22 (dd, 1 H), 8.07 (broad d, 1 H), 7.87 (m, 1 H), 7.79 (m, 2 H), 7.70-7.58 (m, 3 H), 7.45 (s, 1 H), 7.36 (m, 2 H), 7.20 (d, 1 H), 4.49 (q, 2 H), 2.73 (s, 3 H), 1.45 (t, 3 H) ppm. ESI mass spectrum analysis m/z 533.2 (M+H)+.

Part E. reparation of ethyl 1-[3-(aminomethyl)phenyl]-5-[(3-fluoro-2'-methylsulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole-3-carboxylate, trifluoroacetic acid salt.

To a solution of ethyl 1-[(3-cyano)phenyl]-5-[(3-fluoro)-(2'-methylsulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole-3-carboxylate (0.20 g, 0.38 mmol) in 100 mL of absolute ethanol was added 2 mL of trifluoroacetic acid and 50 mg of 10% palladium on carbon catalyst. This mixture was stirred under 50 psi of hydrogen on a Parr apparatus for 24 h. The mixture was filtered through a pad of celite and concentrated in vacuo. The residue was purified by prep HPLC (C18 reverse phase column, elution with a H₂ O/CH₃ CN gradient with 0.5% TFA) and lyophilized to afford 130 mg (53%) of the title compound as a white powder. ¹ HNMR(DMSO-d₆) δ: 9.76 (s, 1 H), 8.64 (broad s, 3 H), 7.94 (d, 1 H), 7.67 (m, 1 H), 7.50-7.37 (m, 5 H), 7.28 (m, 2 H), 7.12 (d, 1 H), 7.05 (dd, 1 H), 6.94 (d, 1 H), 4.21 (q, 2 H), 3.88 (broad s, 2 H), 2.51 (s, 3 H), 1.19 (t, 3 H) ppm. ESI mass spectrum analysis m/z 537.2 (M+H)+.

EXAMPLE 245 1-[3-(aminomethyl)phenyl]-5-[(3-fluoro-2'-methylsulfonyl-[1,1']-biphen-4-yl) aminocarbonyl]pyrazole-3-carboxylic acid, trifluoroacetic acid salt.

To a solution of ethyl 1-[3-(aminomethyl)-phenyl]-5-[(3-fluoro-2'-methylsulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole-3-carboxylate, trifluoroacetic acid salt (0.03 g, 0.05 mmol) in 5 mL of 1:1 ethanol/water was added potassium hydroxide (0.013 g, 0.23 mmol). This mixture was stirred at room temperature for 3 h and then was acidified by the addition of several drops of trifluoroacetic acid. The reaction was concentrated in vacuo and the residue was purified by prep HPLC (C18 reverse phase column, elution with a H₂ O/CH₃ CN gradient with 0.5% TFA) and lyophilized to afford 15 mg (52%) of the title compound as a white powder. ¹ HNMR(DMSO-d₆) δ: 10.60 (s, 1 H), 8.19 (broad s, 3 H), 8.06 (d, 1 H), 7.75 (m, 1 H), 7.69-7.51 (m, 5 H), 7.50 (m, 2 H), 7.39 (d, 1 H), 7.34 (dd, 1 H), 7.21 (d, 1 H), 4.11 (broad s, 2 H), 2.90 (s, 3 H) ppm. ESI mass spectrum analysis m/z 509.2 (M+H)+.

EXAMPLE 246 1-3-(aminomethyl)phenyl]-3- [aminocarbonyl]-5-[3-fluoro-(2'-methylsulfonyl-[1,1']-biphen-4-yl) aminocarbonyl]pyrazole, trifluoroacetic acid salt.

Part A. Preparation of ethyl 1-[3-(N-(tert-butyloxycarbonyl)aminomethyl)-phenyl]-5-[3-fluoro-(2'-methylsulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole-3-carboxylate.

To a solution of ethyl 1-[3-(aminomethyl)-phenyl]-5-[3-fluoro-(2'-methylsulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole-3-carboxylate from Example 244 (0.26 g, 0.40 mmol) in 10 mL of methylene chloride was added di-tert-butyl dicarbonate (0.09 g, 0.40 mmol) and 4-dimethylaminopyridine (0.15 g, 1.20 mmol). The resulting mixture was allowed to stir at room temperature for 18 h. The reaction was diluted with ethyl acetate and then was washed with 10% aq HCl, sat'd aq sodium bicarbonate and brine, dried (MgSO₄) and concentrated in vacuo. The residue was purified by flash chromatography (elution with 2:1 hexanes/ethyl acetate) to afford the 0.24 g (80%) of the title compound. ¹ HNMR(CDCl₃) δ: 8.28 (t, 1 H), 8.14 (d, 1 H), 7.89 (broad s, 1 H), 7.56 (m, 2 H), 7.45-7.35 (m, 4 H), 7.30-7.20 (m, 3 H), 7.11 (d, 1 H), 4.86 (broad s, 1 H), 4.40 (q, 2 H), 4.33 (m, 2 H), 2.65 (s, 3 H), 1.40 (t, 3 H), 1.37 (s, 9 H) ppm. ESI (-ve) mass spectrum analysis m/z (relative intensity) m/z 635.2 (M-H, 100).

Part B. Preparation of 1-[3-(aminomethyl)-phenyl]-3-[aminocarbonyl]-5-[3-fluoro-(2'-methylsulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole, trifluoroacetic acid salt.

To a solution of ethyl 1-[3-(N-(tert-butyloxycarbonyl)aminomethyl)-phenyl]-5-[3-fluoro-(2'-methylsulfonyl-[1,1']-biphenyl-4-yl)aminocarbonyl]pyrazole-3-carboxylate (0.24 g, 0.38 mmol) in 20 mL of 1:1 tetrahydrofuran/water was added potassium hydroxide (0.08 g, 1.5 mmol). The resulting mixture was stirred at 60° C. for 1 h and then was cooled and concentrated in vacuo. The residue was diluted with water and extracted with 1:1 hexane/ethyl acetate. The organics were discarded. The aqueous layer was acidified with aq HCl and extracted with ethyl acetate. The extracts were washed with brine, dried (MgSO₄) and concentrated in vacuo. The residue was dissolved in 10 mL of acetonitrile, cooled to 0° C. and then there was added triethylamine (0.10 mL, 0.71 mmol) and iso-butyl chloroformate (0.067 mL, 0.52 mmol). This mixture was allowed to stir for 30 min and then there was added ammonia (0.95 mL of a 2 M solution in methanol, 1.88 mmol) and the reaction was allowed to stir with warming to room temperature for 18 h. The reaction mixture was diluted with ethyl acetate and then was washed with 10% aq HCl, sat'd aq sodium bicarbonate and brine, dried (MgSO₄) and concentrated in vacuo. The residue was dissolved in 5 mL of trifluoroacetic acid and stirred at room temperature for 2 h and then was concentrated in vacuo. The residue was purified by prep HPLC (C18 reverse phase column, elution with a H₂ O/CH₃ CN gradient with 0.5% TFA) and lyophilized to afford 115 mg (40%) of the title compound as a white powder. ¹ HNMR(DMSO-d₆) δ: 9.53 (s, 1 H), 8.78 (broad s, 3 H), 8.04 (d, 1 H), 7.86 (m, 1 H), 7.64 (s, 1 H), 7.52 (m, 1 H), 7.42 (m, 2 H), 7.37 (m, 3 H), 7.20 (d, 1 H), 7.17 (m, 2 H), 7.04 (d, 1 H), 6.15 (broad s, 1 H), 3.99 (broad s, 2 H), 2.60 (s, 3 H) ppm. ESI (+ve) mass spectrum analysis m/z (relative intensity) (ESI) m/z 508.2 (M+H, 100).

EXAMPLE 247 Ethyl 1-[3-(aminomethyl)-phenyl]-3-trifluoromethyl-5-[(3-fluoro-2'-methylsulfonyl- [1,1']-biphen-4-yl) aminocarbonyl]pyrazole-4-carboxylate, trifluoroacetic acid salt.

Part A. Preparation of N-(3-cyanophenyl)-trifluoroacetohydrazonoyl bromide.

To a solution of 3-hydrazinobenzonitrile HCl salt (1.3 g, 7.66 mmol) in 20 mL of absolute ethanol was added trifluoroacetaldehyde ethyl hemiacetal (1.33 g, 9.19 mmol). The resulting mixture was allowed to stir at 80° C. for 18 h and then the reaction was cooled and concentrated in vacuo. The residue was dissolved in 10 mL of dimethylformamide and then there was added N-bromosuccinimide (1.36 g, 7.66 mmol). The solution was allowed to stir at room temperature for 18 h. The reaction was diluted with ethyl acetate, washed with water, sat'd aq sodium bicarbonate and brine, dried (MgSO₄) and concentrated in vacuo to yield 2.1 g (95%) of the title compound which was sufficiently pure to be used without purification. ¹ HNMR(CDCl₃) δ: 8.16 (broad s, 1 H), 7.47-7.30 (m, 4 H) ppm.

Part B. Preparation of ethyl 3-(2-furyl)-3-oxopropanoate.

To a suspension of hexane-washed sodium hydride (3.5 g of 60% dispersion in mineral oil, 90.8 mmol) in 200 mL of tetrahydrofuran was added diethyl carbonate (10.7 g, 90.8 mmol) and 2-acetylfuran (5.0 g, 45.4 mmol). The resulting mixture was stirred at 70° C. for 1 h and then was cooled to room temperature and quenched by the slow addition of 10% aq HCl. The tetrahydrofuran was removed in vacuo and the aqueous was extracted with ethyl acetate. The organics were washed with water and brine, dried (MgSO₄) and concentrated in vacuo to yield 6.9 g (83%) of the title compound which was sufficiently pure to be used without purification. ¹ HNMR(CDCl₃) δ: 7.61 (t, 1 H), 7.27 (dd, 1 H), 6.57 (dd, 1 H), 4.20 (q, 2 H), 3.84 (s, 2 H), 1.25 (t, 3 H) ppm.

Part C. Preparation of ethyl 1-[(3-cyano)phenyl]-3-trifluoromethyl-5-[furyl-2-yl]pyrazole-4-carboxylate.

To a solution of ethyl 3-(2-furyl)-3-oxopropanoate (1.87 g, 10.26 mmol) in 20 mL of absolute ethanol was added sodium ethoxide (2.6 mL of a 21% solution in ethanol, 6.84 mmol). Then there was added N-(3-cyanophenyl)-trifluoroacetohydrazonoyl bromide (1.0 g, 3.42 mmol) in absolute ethanol. The resulting mixture was stirred at room temperature for 3 h and then was diluted with ether. The layers were separated and the organics were washed with water, sat'd sodium carbonate and brine, dried (MgSO₄) and concentrated in vacuo. The residue was purified by flash chromatography (elution with 4:1 hexanes/ethyl acetate) to afford 0.80 g (63%) of the title compound. ¹ HNMR(CDCl₃) δ: 7.71 (m, 1 H), 7.60 (m, 1 H), 7.53 (m, 2 H), 7.44 (d, 1 H), 6.95 (d, 1 H), 6.55 (dd, 1 H), 4.33 (q, 2 H), 1.32 (t, 3 H) ppm.

Part D. Preparation of ethyl 1-[(3-cyano)phenyl]-3-trifluoromethyl-5-[carboxy]pyrazole-4-carboxylate.

To a solution of ethyl 1-[(3-cyano)phenyl]-3-trifluoromethyl-5-[furyl-2-yl]pyrazole-4-carboxylate (0.75 g, 2.0 mmol) in 30 mL of a 2:3:2 mixture of acetonitrile/water/carbon tetrachloride was added sodium periodate (1.92 g, 9.0 mmol) and ruthenium trichloride hydrate (0.008 g, 0.04 mmol). The mixture was stirred at room temperature for 18 h and then was concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with brine, dried (MgSO₄) and concentrated in vacuo. This residue was dissolved in 1:1 hexanes/ethyl acetate and extracted with sat'd aq sodium carbonate. The aqueous layer was acidified with HCl and then was extracted with ethyl acetate. These ethyl acetate extracts were washed with brine, dried (MgSO₄) and concentrated in vacuo to afford 0.40 g (56%) of the title compound which was sufficiently pure to be used without purification. ¹ HNMR(CDCl₃) δ: 7.82 (m, 1 H), 7.71 (d, 1 H), 7.64 (m, 2 H), 4.55 (q, 2 H), 1.47 (t, 3 H) ppm. ESI (-ve) mass spectrum analysis m/z (relative intensity) 352.1 (M-H, 100).

Part E. Preparation of ethyl 1-[(3-cyano)phenyl]-3-trifluoromethyl-5-[(3-fluoro-2'-methylsulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole-4-carboxylate.

To a solution of ethyl 1-[(3-cyano)phenyl]-3-trifluoromethyl-5-[carboxy]pyrazole-4-carboxylate (0.33 g, 0.93 mmol) in 10 mL of methylene chloride was added oxalyl chloride (0.12 mL, 1.4 mmol) and about 3 drops of dimethylformamide. This solution was allowed to stir at room temperature for 6 h and then was concentrated in vacuo. The residue was dissolved in methylene chloride and then there was added 4-dimethylaminopyridine (0.34 g, 2.79 mmol) and (2-fluoro-2'-methylsulfonyl-[1,1']-biphen-4-yl)amine hydrochloride (0.28 g, 0.93 mmol). The resulting mixture was stirred at room temperature for 18 h. The reaction was diluted with ethyl acetate, washed with 10% aq HCl, sat'd aq sodium bicarbonate and brine, dried (MgSO₄) and concentrated in vacuo. The residue was purified by flash chromatography (elution with 2:1 hexanes/ethyl acetate) to afford the 0.25 g (45%) of the title compound. ¹ HNMR(CDCl₃) δ: 11.27 (s, 1 H), 8.29 (t, 1 H), 8.21 (d, 1 H), 7.79 (m, 2 H), 7.67-7.52 (m, 4 H), 7.40-7.30 (m, 2 H), 7.18 (d, 1 H), 4.51 (q, 2 H), 2.73 (s, 3 H), 1.45 (t, 3 H) ppm. ESI (+ve) mass spectrum analysis m/z (relative intensity) 623.1 (M+Na, 100).

Part F. Preparation of ethyl 1-[3-(aminomethyl)-phenyl]-3-trifluoromethyl-5-[(3-fluoro-2'-methylsulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole-4-carboxylate, trifluoroacetic acid salt.

To a solution of ethyl 1-[(3-cyano)phenyl]-3-trifluoromethyl-5-[(3-fluoro-2'-methylsulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole-4-carboxylate (0.13 g, 0.22 mmol) in 20 mL of absolute ethanol was added conc. HCl (0.018 mL, 0.22 mmol) and 20 mg of 10% palladium on carbon catalyst. This mixture was stirred under 1 atm of hydrogen for 18 h. The mixture was filtered through a pad of celite and concentrated in vacuo. The residue was purified by prep HPLC (C18 reverse phase column, elution with a H₂ O/CH₃ CN gradient with 0.5% TFA) and lyophilized to afford 35 mg (21%) of the title compound as a white powder. ₁ HNMR(DMSO-d₆) δ: 11.22 (s, 1 H), 8.21 (broad s, 3 H), 8.06 (dd, 1 H), 7.87 (t, 1 H), 7.80-7.40 (m, 6 H), 7.38 (m, 2 H), 7.22 (dd, 1 H), 4.26 (q, 2 H), 4.13 (broad q, 2 H), 2.91 (s, 3 H), 1.14 (t, 3 H) ppm. ESI (+ve) mass spectrum analysis m/z (relative intensity) (AP+) 605.2 (M+H, 100).

EXAMPLE 248 1-[3-(aminomethyl)phenyl]-5-[(3-fluoro-2'-methylsulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-(methylthio)pyrazole, trifluoroacetic acid salt

Part A: Preparation of 1-[3-(t-butoxycarbonylaminomethyl)phenyl]-5-[(3-fluoro-2'-methylsulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-(methylthio)pyrazole.

DMF (3 drops) was added to 1-[3-(t-butoxycarbonylaminomethyl)phenyl]-3-(methylthio)pyrazole-5-carboxylic acid (553 mg, 1.5 mmol) and oxalyl chloride (260 μL, 3.0 mmol) in dry CH₂ Cl₂ (30 mL). The resulting solution was stirred at room temperature for 1 h. and evaporated. The resulting solid was redissolved in dry CH₂ Cl₂ (30 mL), and 4-dimethylaminopyridine (585 mg, 4.8 mmol) was added. After stirring 4 min., 4-amino-3-fluoro-2'-methylsulfonyl-[1,1']-biphenyl, hydrochloride (530 mg, 1.8 mmol) was added portionwise over 5 min., and stirred 22 h. The reaction was extracted once with sat. NaHCO₃, then once with a cooled solution of 0.1 M HCl. The organic layer was dried over NgSO₄, filtered, and evaporated. The crude product was chromatographed on silica gel (40-50% EtOAc/hexanes) to yield the desrired product (376 mg, 41%). ¹ HNMR(CDCl₃) δ: 8.38 (bt, 1 H), 8.21 (dd, 1 H, J=7.7, J'=1.1), 7.81 (bs, 1 H), 7.65 (td, 1 H, J=7.4, J'=1.4), 7.58 (td, 1 H, J=7.7, J'=1.5), 7.43 (m, 4 H), 7.32 (m, 2 H), 7.17 (d, 1 H, J=8.8), 6.84 (s, 1 H), 4.90 (bs, 1 H), 4.39 (d, 2 H, J=6.3), 2.72 (s, 3 H), 2.60 (s, 3 H), 1.45 (s, 9 H) ppm.

Part B: Preparation of 1-[3-(aminomethyl)phenyl]-5-[(3-fluoro-2'-methylsulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-(methylthio)pyrazole.

1-[3-(t-Butoxycarbonylaminomethyl)phenyl]-5-[(3-fluoro-2'-methylsulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-(methylthio)pyrazole (287 mg, 0.47 mmol) was dissolved in CH₂ Cl₂ (5 mL) and TFA (5 mL) and stirred at room temperature for 16 h. The reaction was evaporated and purified by prep. HPLC (10-70% MeCN/H₂ O/0.05% TFA) to yield the desired product (271 mg, 92%). (DMSO-d₆) δ: 10.60 (s, 1 H), 8.25 (bs, 2 H), 8.13 (d, 1 H, J=8.1), 7.82 (td, 1 H, J=7.3, J'=1.5), 7.74 (m, 3 H), 7.48 (m, 5 H), 7.28 (d, 1 H, J=8.4), 7.23 (s, 1 H), 4.16 (d, 2 H, J=5.8), 2.97 (s, 3 H), 2.61 (s, 3 H) ppm. APcI mass spectrum analysis m/z=511 (M+H, 100).

EXAMPLE 249 1-[3-(aminomethyl)phenyl]-5-[(3-fluoro-2'-meethylsulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-(methylsulfonyl)pyrazole, trifluoroacetic acid salt

MCPBA (110 mg, 57-86%) was added t 1-[3-(t-butoxycarbonylaminomethyl)phenyl]-5-[(3-fluoro-2'-ethylsulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-(methylthio)pyrazole (89 mg, 0.15 mmol) in CH₂ Cl₂ (5 mL) and stirred at room temperature for 6 h. The reaction was extracted once with sat. Na₂ SO₃, then once with sat. NaHCO₃. The organic layer was dried over Na₂ SO₄, filtered, and evaporated. The crude product was redissolved in CH₂ Cl₂ (1.5 mL) and TFA (1.5 mL) and stirred at room temperature for 5 h. The resulting solution was evaporated and purified by prep. HPLC (10-70% MeCN/H₂ O/0.05% TFA) to yield the desired product. ¹ HNMR(DMSO-d₆) δ: 10.75 (s, 1 H), 8.20 (bs, 3 H), 8.06 (dd, 1 H, J=8.0, J'=1.5), 7.70 (m, 5 H), 7.56 (m, 3 H), 7.38 (m, 2 H), 7.20 (dd, J=8.1 and 1.7 Hz, 1 H), 4.11 (d, 2 H, J=5.5 ), 3.36 (s, 3 H), 2.91 (s, 3 H) ppm. ESI mass spectrum analysis m/z (relative intensity) 543 (M+H, 100).

EXAMPLE 250 1-[3-(aminomethyl)phenyl]5-[(4-(5-(metho yaminocarbonyl)imidazol-1-yl)phen-1-yl)aminocarbonyl]3-trifluoromethylpyrazole, trifluoroacetic acid salt.

Part A: A solution of 4-amino-nitrobenzene (5.3 g, 38.4 mmol) in ethyl alcohol (50 mL) was treated with n-butyl glyoxylate (10.0 g, 76.9 mmol). After stirring at reflux for 18 h, the reaction mixture was concentrated at reduced pressure. The residue was carried to the next step without purification. To the solution of the imine (10.0 g, 40.0 mmol) in methyl alcohol (50 mL) was added potassium carbonate (11.0 g, 80.0 mmol) and tosylmethyl isocyanate (11.7 g, 60.0 mmol). The solution was stirred for 1 h at rt, then the solvent was removed under reduced pressure. The residue was treated with saturated sodium chloride solution and the mixture was extracted with methylene chloride. The organic extract was concentrated and triturated with methyl alcohol. The precipitate was collected and dried to afford an imidazole (5.9 g, 59%, 2 steps). Reduction to the aniline was accomplished in MeOH and 10% of Pd/C at 50 psi over 18 h. MS (ESI) m/z (rel. intensity), 216 (M⁺ +H, 100).

Part B: The product from part A was then coupled to 1-(3-cyanophenyl)-3-trifluoromethylpyrazole carboxylic acid via the acid chloride methodology previously described. The product was purified via silica gel column chromatography (hexane:ethyl acetate, 4:3) to afford pure coupled product. ESI mass spectrum analysis m/z (relative intensity) 481 (M⁺ +H, 100).

Part C: The product from part B (200 mg, 0.4 mmol) in THF (3 mL) was treated with 1 N NaOH (0.8 mL, 0.8 mmol). The resultant reaction mixture was stirred for 18 h at rt, then acidified to pH 7 with 1 N HCl, extracted with ethyl acetate, dried over magnesium sulfate and concentrated. The resultant acid (100 mg, 0.2 mmol) was dissolved in THF (5 mL), treated with DIEA (0.001 mL, 0.6 mmol), methoxylamine hydrochloride (0.030 g, 0.36 mmol) and TBTU (83 mg, 0.2 mmol) and stirred for 18 h at rt. The residue was treated with water and the mixture was extracted with ethyl acetate, dried over sodium sulphate and concentrated. Purification by silca gel flash chromatography (methanol/methylene chloride, 1:9) afforded the methoxy hydroxamate intermediate (60 mg, 56%). ESI mass spectrum analysis m/z (rel. intensity), 496 (M³⁰ +H, 100). Reduction of the nitrile to the benzylamine was then accomplished via standard conditions. ¹ HNMR(CD3OD) δ: 3.74 (s, 3 H), 4.21 (s, 2 H), 7.43 (s, 1 H), 7.46 (m, 2 H), 7.60 (m, 3 H), 7.78 (m, 2 H), 7.80 (m, 3 H) ppm. ESI mass spectrum analysis m/z (relative intensity) 442 (M⁺ +H, 100).

EXAMPLE 251 1-(3-aminomethylphenyl)-5-[(4-(5-methyl-1,2,3-triazol-1-yl)phen-1-yl)aminocarbonyl]-3-trifluoromethylpyrazole, trifluoroacetic acid salt.

Part A: A solution of 4-tert-butyl-[1-(4-nitrophenyl)]5-methyl-1,2,3-tiazol-1-yl-carboxylate (Maybridge Chemical Company, 0.5 g, 1.6 mmol) in TFA (10 mL) was refluxed over 18 h. The reaction mixture was concentrated at reduced pressure. The residue was then reduced to the aniline via standard conditions without purification. ¹ HNMR(CDCl₃) δ: 2.36 (s, 3 H), 6.83 (d, J=8.8 Hz, 2 H), 7.23 (d, J=8.8 Hz, 2 H), 7.80 (s, 1 H) ppm. ESI mass spectrum analysis m/z (relative intensity) 175 (M⁺ +H, 100).

Part B: The intermediate was then coupled to 1-(3-cyanophenyl)-3-trifluoromethylpyrazole carboxylic acid via the acid chloride methodology previously described followed by reduction of the nitrile to the benzylamine and purification via HPLC under reverse phase techniques and lyophilization to afford the title compound as a colorless solid. ¹ HNMR(CD3OD) δ: 2.35 (s, 3 H), 4.22 (s, 2 H), 7.51 (d, J=9.5 Hz, 2 H), 7.55 (s, 1 H), 7.60 (m, 3 H), 7.65 (s, 1 H), 7.71 (s, 1 H), 7.89 (d, J=9.2 Hz, 2 H) ppm. ESI mass spectrum analysis m/z (relative intensity) 500 (M⁺ +H, 100).

                                      TABLE 1a                                     __________________________________________________________________________      ##STR50##                                                                                         ##STR51##                                                   ##STR52##                                                                                         ##STR53##                                                   ##STR54##                                                                                         ##STR55##                                                   ##STR56##                                                                                         ##STR57##                                                   ##STR58##                                                                     Ex                                                                               Ring M                                                                               Z    R.sup.1a                                                                           A'  A"                                                                               B          MS                                           __________________________________________________________________________      1                                                                               pyrrole-a                                                                            CONH  H   CH                                                                                CH  2-H.sub.2 NSO.sub.2 --C.sub.6 H.sub.4  460.3                                2 pyrrole-a CONH H CH CH 2-t-Bu--HNSO.sub.2                                   --C.sub.6 H.sub.4 516.4                                                         3 pyrrole-a CONH Br CH CH 2-H.sub.2 NSO.sub.2                                 --C.sub.6 H.sub.4 538.2                                                         4 pyrrole-a CONH H N CH 2-H.sub.2 NSO.sub.2                                   --C.sub.6 H.sub.4 461.3                                                         5 pyrrole-b CONH benzyl CH CH 2-H.sub.2 NSO.sub.2                             --C.sub.6 H.sub.4 550.3                                                         6 pyrrole-b CONH benzyl CH CH 2-t-Bu--HNSO.sub.2                              --C.sub.6 H.sub.4 606.5                                                         7 imidazole-b CONH H CH CH 2-H.sub.2 NSO.sub.2                                --C.sub.6 H.sub.4 461.1                                                         8 imidazole-b CONH H CH CH 2-t-Bu--HNSO.sub.2                                 --C.sub.6 H.sub.4 517.2                                                         9 imidazole-a CONH H CH CH 2-H.sub.2 NSO.sub.2                                --C.sub.6 H.sub.4 461.3                                                        10 pyrazole CONH CH.sub.3 CH CH 2-H.sub.2 NSO.sub.2                            --C.sub.6 H.sub.4 475.2                                                        11 pyrazole NHCO CH.sub.3 CH CH 2-H.sub.2 NSO.sub.2                            --C.sub.6 H.sub.4 475.2                                                        12 pyrazole CONH CH.sub.3 CH CH 2-(5'-CF.sub.3                                 - 532.4                                                                              tetrazo-1'-                                                                    yl)C.sub.6 H.sub.4                                                       13 4-Cl- CONH CH.sub.3 CH CH 2-t-Bu-NHSO.sub.2                                 --C.sub.6 H.sub.4 509.1                                                         pyrazole                                                                      14 pyrazole CONH CF.sub.3 CH CH 2-H.sub.2 NSO.sub.2                            --C.sub.6 H.sub.4 529.0                                                        15 4-CH.sub.3 O- CONH CF.sub.3 CH CH 2-H.sub.2                                 NSO.sub.2 --C.sub.6 H.sub.4 559.4                                               pyrazole                                                                      16 pyrazole CONH CH.sub.3 CH CH 1-imidazolyl 386.2                             17 pyrazole CONH CH.sub.3 CH CH --O-2'-CH.sub.3                                SO.sub.2 --C.sub.6 H.sub.4 490.3                                               18 pyrazole COCH.sub.2 CH.sub.3 CH CH 2-H.sub.2                                NSO.sub.2 --C.sub.6 H.sub.4 474.2                                              19 1,2,3- CONH H CH CH 2-H.sub.2 NSO.sub.2 --C.sub.6                           H.sub.4 463.1                                                                   triazole                                                                      20 tetrazole CONH -- CH CH 2-CF.sub.3 --C.sub.6                                H.sub.4 452.2                                                                  21 tetrazole SCH.sub.2 -- C--Cl CH 2-H.sub.2                                   NSO.sub.2 --C.sub.6 H.sub.4 500.2                                              22 tetrazole SOCH.sub.2 -- C--Cl CH 2-H.sub.2                                  NSO.sub.2 --C.sub.6 H.sub.4 516.2                                              23 tetrazole SO.sub.2 CH.sub.2 -- C--Cl CH 2-H.sub.2                           NSO.sub.2 --C.sub.6 H.sub.4 532.2                                              24 tetrazole CONH -- CH CH 2-H.sub.2 NSO.sub.2                                 --C.sub.6 H.sub.4 463.3                                                        25 pyrazole CONH CH.sub.3 N CH 2-H.sub.2 NSO.sub.2                             --C.sub.6 H.sub.4 476.3                                                        26 pyrazole CONH CH.sub.3 N N 2-H.sub.2 NSO.sub.2                              --C.sub.6 H.sub.4 477.2                                                        27 pyrazole CONH CH.sub.3 C--Cl CH 2-H.sub.2                                   NSO.sub.2 --C.sub.6 H.sub.4 509.3                                              28 pyrazole CONH CH.sub.3 C--F CH 2-H.sub.2 NSO.sub.2                           --C.sub.6 H.sub.4 493.2                                                       29 pyrazole CONH CH.sub.3 CH CH 2-H.sub.2 NSO.sub.2                            -4-F--C.sub.6 H.sub.3 493.3                                                    30 pyrazole CONH CH.sub.3 CH CH 2-CF.sub.3 --C.sub.6                           H.sub.4 464.3                                                                  31 pyrazole CONH CH.sub.3 C--Cl CH 2-CF.sub.3                                  --C.sub.6 H.sub.4 498.3                                                        32 pyrazole CONH CH.sub.3 C--F CH 2-CF.sub.3                                   --C.sub.6 H.sub.4 482.2                                                        33 pyrazole CONH CH.sub.3 N CH 2-CF.sub.3 --C.sub.6                            H.sub.4 465.3                                                                  34 pyrazole CONH CH.sub.3 CH CH 2-F--C.sub.6                                   H.sub.4 414.3                                                                  35 pyrazole CONH CH.sub.3 C--Cl CH 2-F--C.sub.6                                H.sub.4 448.0                                                                  36 pyrazole CONH CH.sub.3 CH CH 2-CH.sub.3 SO.sub.2                            --C.sub.6 H.sub.4 474.3                                                        37 pyrazole CONCH.sub.3 CH.sub.3 CH CH 2-H.sub.2                               NSO.sub.2 --C.sub.6 H.sub.4 489.3                                              38 pyrazole CONH C.sub.4 H.sub.9 CH CH 2-H.sub.2                               NSO.sub.2 --C.sub.6 H.sub.4 517.4                                              39 pyrazole CONH C.sub.4 H.sub.9 N CH 2-H.sub.2                                NSO.sub.2 --C.sub.6 H.sub.4 518.2                                              40 pyrazole CONH C.sub.4 H.sub.9 N CH 2-CF.sub.3                               --C.sub.6 H.sub.4 506.3                                                        41 pyrazole CONH CF.sub.3 CH CH 2-CH.sub.3 SO.sub.2                            --C.sub.6 H.sub.4 528.2                                                        42 pyrazole CONH CF.sub.3 CH CH 2-CF.sub.3 --C.sub.6                           H.sub.4 518.2                                                                  43 4-CH.sub.3 O- CONH CF.sub.3 CH CH 2-CF.sub.3                                --C.sub.6 H.sub.4 548.3                                                         pyrazole                                                                      44 pyrazole CONH CH.sub.3 CH CH CF.sub.3 388.2                                 45 imidazole- CONH 4-CH.sub.3 CH CH 2-H.sub.2                                  NSO.sub.2 --C.sub.6 H.sub.4 475.3                                               a                                                                             46 1,2,3- CONH H N CH 2-H.sub.2 NSO.sub.2 --C.sub.6                            H.sub.4 463.3                                                                   triazole                                                                      47 1,2,3- CONH H CH CH 2-CF.sub.3 --C.sub.6 H.sub.4 4                          51.3                                                                            triazole                                                                      48 1,2,4- CONH CF.sub.3 CH CH 2-H.sub.2 NSO.sub.2                              --C.sub.6 H.sub.4 530.3                                                         triazole                                                 __________________________________________________________________________

                                      TABLE 1b                                     __________________________________________________________________________      ##STR59##                                                                                         ##STR60##                                                                                  ##STR61##                                       ##STR62##                                                                                         ##STR63##                                                                                  ##STR64##                                       ##STR65##                                                                                         ##STR66##                                                                                  ##STR67##                                      Unless otherwise indicated, D is at the meta position and is                   amidino (AM) and R is absent.                                                  Ex M           Z     R.sup.1a A-B          MS                                  __________________________________________________________________________     49 pyrazole    CONH  methyl   4-(4'-chlorophenyl)-                                                                        437.1                                                             thiazol-2-yl                                     50 pyrazole    CONH  methyl   2'-CF.sub.3 S-biphenyl                                                                      496.1                               51 pyrazole    CONH  methyl   2'-CF.sub.3 S(O)-biphenyl                                                                   512                                 52 pyrazole    CONH  methyl   2'-CF.sub.3 S(O).sub.2 -biphenyl                                                            528.1                               53 pyrazole    CONH  methyl   4-carboxymethyl-C.sub.6 H.sub.4                                                             378.2                               54 pyrazole    CONH  methyl   4-N,N-(CH.sub.3).sub.2 NC(O)--C.sub.6                                          H.sub.4      391                                 55 pyrazole    CONH  methyl   4-N,N-(CH.sub.3).sub.2 NS(O).sub.2 --C.sub.6                                    H.sub.4     426                                 56 pyrazole    CONH  methyl   4-t-Bu--HNSO.sub.2 --C.sub.6 H.sub.4                                                        455                                 57 pyrazole    CONH  methyl   4-H.sub.2 NSO.sub.2 --C.sub.6 H.sub.4                                                       381.3                               58 pyrazole    CONH  methyl   4-CF.sub.3 --C.sub.6 H.sub.4                                                                388.1                               59 pyrazole    CONH  methyl   4-benzylsulfonyl-                                                                           481.2                                                             piperidyl                                        60 pyrazole    CONCH.sub.3                                                                          methyl   2'-H.sub.2 NSO.sub.2 -biphenyl                                                              489.2                               61 pyrazole    CONH  methyl   4'-F-biphenyl                                                                               489.2                               62 pyrazole    CONH  methyl   5-(2'-H.sub.2 NSO.sub.2 --C.sub.6 H.sub.4)-                                                 476.1                                                             pyridin-2-yl                                     63 pyrazole    CONH  methyl   5-(2'-H.sub.2 NSO.sub.2 --C.sub.6 H.sub.4)-                                                 459.1                                  (D = --CN)                 pyridin-2-yl                                     64 pyrazole    CONH  methyl   2'-CF.sub.3 -biphenyl                                                                       464.2                               65 pyrazole    CONH  methyl   2'-H.sub.2 NSO.sub.2 -biphenyl                                                              476.1                                  (D = CONH.sub.2)                                                            66 pyrazole    CONH  methyl   2'-H.sub.2 NSO.sub.2 -3-                                                                    509.1                                                             chlorobiphenyl                                   67 pyrazole    CONH  methyl   2'-CF.sub.3 -3-                                                                             498.1                                                             chlorobiphenyl                                   68 pyrazole    CONH  C.sub.4 H.sub.9                                                                         2'-H.sub.2 NSO.sub.2 -biphenyl                                                              517.2                               69 pyrazole    CONH  C.sub.4 H.sub.9                                                                         2'-CF.sub.3 -biphenyl                                                                       507.2                               70 pyrazole    CONH  C.sub.4 H.sub.9                                                                         5-(2'-H.sub.2 NSO.sub.2 --C.sub.6 H.sub.4)-                                                 518.2                                                             pyridin-2-yl                                     71 4-CH.sub.3 O-                                                                              CONH  CF.sub.3 2'-CF.sub.3 -biphenyl                                                                       548.2                                  pyrazole                                                                    72 pyrazole    CONH  CF.sub.3 2'-CF.sub.3 -biphenyl                                                                       518.1                               73 pyrazole    CONH  CF.sub.3 2'-SO.sub.2 CH.sub.3 -biphenyl                                                              528.1                               74 pyrazole    CONH  methyl   2'-H.sub.2 NSO.sub.2 -3-Br-                                                                 553.1                                                             biphenyl                                         75 pyrazole    CONH  methyl   2'-H.sub.2 NSO.sub.2 -3-Br-                                                                 554.1                                  (D = CONH.sub.2)           biphenyl                                         76 pyrazole    COCH.sub.2                                                                           methyl   2'-H.sub.2 NSO.sub.2 -biphenyl                                                              474.2                               77 pyrazole    CONH  methyl   5-(2'-H.sub.2 NSO.sub.2 --C.sub.6 H.sub.4)-                                                 477.1                                  (D = CONH.sub.2)           pyridin-2-yl                                     78 pyrazole    CONH  CF.sub.3 5-(2'-t-Bu--HNSO.sub.2 --C.sub.6 H.sub.4)-                                                  587.2                                                             pyrimidin-2-yl                                   79 pyrazole    CONH  CF.sub.3 5-(2'-H.sub.2 NSO.sub.2 --C.sub.6 H.sub.4)-                                                 531.1                                                             pyrimidin-2-yl                                   80 pyrazole    CONH  CF.sub.3 5-(2'-H.sub.2 NSO.sub.2 --C.sub.6 H.sub.4)-                                                 532.1                                  (D = CONH.sub.2)           pyrimidin-2-yl                                   81 pyrazole    CONH  CF.sub.3 4'-imidazol-1-yl-C.sub.6 H.sub.4                                                            440.1                                  (D = --CN)                                                                  82 pyrazole    CONH  CF.sub.3 4'-morpholin-1-yl-C.sub.6 H.sub.4                                                           459.2                               83 pyrazole    CONH  CF.sub.3 4'-morpholin-1-yl-C.sub.6 H.sub.4                                                           460.1                                  (D = CONH.sub.2)                                                            84 pyrazole    CONH  CF.sub.3 5-(2'-H.sub.2 NSO.sub.2 --C.sub.6 H.sub.4)-                                                 530.1                                                             pyridin-2-yl                                     85 pyrazole    CONH  CF.sub.3 5-(2'-H.sub.2 NSO.sub.2 --C.sub.6 H.sub.4)-                                                 531.1                                  (D = CONH.sub.2)           pyridin-2-yl                                     86 pyrazole    CONH  CF.sub.3 4'-(3-methyltetrazol-                                                                       456.2                                                             1-yl)C.sub.6 H.sub.4                             87 pyrazole    NHSO.sub.2                                                                           methyl   2'-naphthyl  406.1                               88 pyrazole    NHSO.sub.2                                                                           methyl   2'-(4-bromo-C.sub.6 H.sub.4)                                                                434.0                               89 pyrazole    CONH  methyl   2'-H.sub.2 NSO.sub.2 -biphenyl                                                              462.2                                  (D = CH.sub.2 NH.sub.2)                                                     90 pyrazole    CONH  CF.sub.3 2'-H.sub.2 NSO.sub.2 -biphenyl                                                              516.1                                  (D = CH.sub.2 NH.sub.2)                                                     91 pyrazole    CONH  methyl   5-(2'-CF.sub.3 --C.sub.6 H.sub.4)pyrid-                                                     465.2                                                             2-yl                                             92 pyrazole    CONH  methyl   5-(2'-H.sub.2 NSO.sub.2 --C.sub.6 H.sub.4)-                                                 477.2                                                             pyrimidin-2-yl                                   93 pyrazole    CONH  methyl   2'-F-biphenyl                                                                               414.2                               94 pyrazole    CONH  methyl   3-Cl-2'-F-biphenyl                                                                          448.1                               95 pyrazole    CONH  methyl   3-F-2'-F-biphenyl                                                                           482.2                               96 pyrazole    CONH  methyl   3-F-2'-H.sub.2 NSO.sub.2 -biphenyl                                                          493.1                               97 pyrazole    CONH  methyl   5-(2'-F--C.sub.6 H.sub.4)pyrid-2-                                                           415.2                                                             yl                                               98 pyrazole    CONH  methyl   5-(2'-t-Bu--NHSO.sub.2 -                                                                    533.2                                                             phenyl)pyrimidin-2-yl                            99 pyrazole    CONH  methyl   5-(2'-H.sub.2 NSO.sub.2 --C.sub.6 H.sub.4)-                                                 579.2                                                             ([1,6]-dihydropyrimid-                                                         2-yl)                                            100                                                                               pyrazole    CONH  methyl   4-pyrid-3'-yl-C.sub.6 H.sub.4                                                               379.2                               101                                                                               pyrazole    CONH  methyl   2-(2'-pyridyl)ethyl                                                                         349.2                               102                                                                               pyrazole    CONH  methyl   3-(C.sub.6 H.sub.4)propyl                                                                   362.2                               103                                                                               pyrazole    CONH  methyl   4-(pyrid-2'-yl)C.sub.6 H.sub.4                                                              397.2                               104                                                                               pyrazole    CONH  methyl   4-(i-propoxy)C.sub.6 H.sub.4                                                                378.2                               105                                                                               pyrazole    CONH  methyl   5-(2'-CF.sub.3 -                                                                            466.2                                                             phenyl)pyrimidin-2-yl                            106                                                                               pyrazole    CONH  methyl   4-(piperidino-SO.sub.2)C.sub.6 H.sub.4                                                      467.2                               107                                                                               pyrazole    CONH  methyl   4-(piperidino-CO)C.sub.6 H.sub.4                                                            431.1                               108                                                                               pyrazole    CONH  methyl   2'-H.sub.2 NSO.sub.2 -biphenyl                                                              493                                    (R = F)                                                                     109                                                                               pyrazole    CONH  methyl   2'-H.sub.2 NSO.sub.2 -biphenyl                                                              494.1                                  (D = CONH.sub.2)                                                               (R = F)                                                                     110                                                                               3-pyrazole  CONH  1-       2'-H.sub.2 NSO.sub.2 -biphenyl                                                              475.3                                                    methyl                                                    111                                                                               pyrazole    CONH  methyl   4-(pyrazol-4'-yl)C.sub.6 H.sub.4                                                            386.3                               112                                                                               pyrazole    CONH  methyl   5-(2'-SO.sub.2 CH.sub.3 --C.sub.6 H.sub.4)-                                                 475.2                                                             pyrid-2-yl                                       113                                                                               pyrazole    CONH  methyl   5-(2'-SO.sub.2 CH.sub.3 --C.sub.6 H.sub.4)-                                                 476.2                                                             pyrimid-2-yl                                     114                                                                               pyrazole    CONH  methyl   5-(2'-SO.sub.2 CH.sub.3 --C.sub.6 H.sub.4)-                                                 459.0                                  (D = --CN)                 pyrimid-2-yl                                     115                                                                               pyrazole    CONH  methyl   5-(2'-SO.sub.2 CH.sub.3 --C.sub.6 H.sub.4)-                                                 477.1                                  (D = CONH.sub.2)           pyrimid-2-yl                                     116                                                                               pyrazole    CONH  methyl   2'-t-Bu--NHSO.sub.2 -biphenyl                                                               490.2                                  (D = N--NH.sub.2 --AM)                                                      117                                                                               pyrazole    CONH  methyl   2'-H.sub.2 NSO.sub.2 -biphenyl                                                              546.2                                  (D = N--NH.sub.2 --AM)                                                      118                                                                               pyrazole    CONH  methyl   2'-t-Bu--NHSO.sub.2 -biphenyl                                                               561.2                                  (D =                                                                           N--Me--N--HO--AM)                                                           119                                                                               pyrazole    CONH  methyl   2'-t-Bu--NHSO.sub.2 -biphenyl                                                               545.2                                  (D = N--Me--AM)                                                             120                                                                               pyrazole    CONH  methyl   2'-H.sub.2 NSO.sub.2 -biphenyl                                                              489.2                                  (D = N--Me--AM)                                                             121                                                                               tetrazole   CONH  --       5-(2'-H.sub.2 NSO.sub.2 --C.sub.6 H.sub.4)-                                                 464.2                                                             pyridin-2-yl                                     122                                                                               tetrazole   CONH  --       5-(2'-H.sub.2 NSO.sub.2 --C.sub.6 H.sub.4)-                                                 465.1                                  (D = CONH.sub.2)           pyridin-2-yl                                     123                                                                               tetrazole   CONH  --       5-(2'-CF.sub.3 --C.sub.6 H.sub.4)-                                                          453.2                                                             pyridin-2-yl                                     124                                                                               tetrazole   CONH  --       4-Br--C.sub.6 H.sub.4                                                                       386.0                               125                                                                               tetrazole   CONH  --       5-(2'-CF.sub.3 --C.sub.6 H.sub.4)-                                                          454.1                                  (D = CONH.sub.2)           pyridin-2-yl                                     126                                                                               tetrazole   CH.sub.2                                                                             --       2'-CF.sub.3 -biphenyl                                                                       423.2                               127                                                                               1-(3-AM-    CONH  methyl   2'-H.sub.2 NSO.sub.2 -biphenyl                                                              489                                    phenyl)-                                                                       methyl-                                                                        pyrazole                                                                    128                                                                               1-(4-AM-    CONH  methyl   2'-H.sub.2 NSO.sub.2 -biphenyl                                                              489                                    phenyl)-                                                                       methyl-                                                                        pyrazole                                                                    129                                                                               imidazole-  CONH  --       2'-H.sub.2 NSO.sub.2 -biphenyl                                                              461                                    a                                                                           130                                                                               imidazole-  CONH  4-       2'-H.sub.2 NSO.sub.2 -biphenyl                                                              475.2                                  a                 methyl                                                    131                                                                               imidazole-  COHN  5-Cl,    2'-H.sub.2 NSO.sub.2 -biphenyl                                                              509.1                                  a                 4-Me                                                      132                                                                               imidazole-  CONH  2-       2'-H.sub.2 NSO.sub.2 -biphenyl                                                              475.1                                  c                 methyl                                                    133                                                                               pyrazole    CONH  methyl   4'-(N-benzimidazol-1-                                                                       436.2                                                             yl)C.sub.6 H.sub.4                               134                                                                               pyrazole    CONH  methyl   4'-(N-benzimidazol-1-                                                                       437.2                                  (D = CONH.sub.2)           yl)C.sub.6 H.sub.4                               135                                                                               pyrazole    CONH  methyl   4-(2'-methylimidazol-                                                                       400.2                                                             1-yl)C.sub.6 H.sub.4                             136                                                                               pyrazole    CONH  methyl   4-(2'-methylimidazol-                                                                       401.2                                  (D = CONH.sub.2)           1-yl)C.sub.6 H.sub.4                             137                                                                               pyrazole    CONH  methyl   4'-(1,2,4-triazol-2-                                                                        387.2                                                             yl)C.sub.6 H.sub.4                               138                                                                               pyrazole    CONH  methyl   4'-cyclohexyl-C.sub.6 H.sub.4                                                               402.2                               139                                                                               pyrazole    CONH  methyl   biphenyl     396.2                               140                                                                               pyrazole    CONH  methyl   4'-morpholino-C.sub.6 H.sub.4                                                               405.2                               141                                                                               pyrazole    CONH  methyl   4'-(2-CF.sub.3 -tetrazol-1-                                                                 456.2                                                             yl)C.sub.6 H.sub.4                               142                                                                               pyrazole    CONH  methyl   4'-(2-CF.sub.3 -tetrazol-1-                                                                 443.2                                  (D = CH.sub.2 NH.sub.2)    yl)C.sub.6 H.sub.4                               143                                                                               pyrazole    CONH  methyl   4-(CH.sub.3).sub.2 NC(O)H--C.sub.6 H.sub.4                                                  406.2                               144                                                                               pyrazole    CONH  methyl   4-(CH.sub.3).sub.2 N--C.sub.6 H.sub.4                                                       391.2                               145                                                                               pyrazole    CONH  methyl   4-(CH.sub.3).sub.2 N--C.sub.6 H.sub.4                                                       392.2                                  (D = CONH.sub.2)                                                            146                                                                               pyrazole    CONH  methyl   4-tetrazol-1-yl-C.sub.6 H.sub.4                                                             388.2                               147                                                                               pyrazole    CONH  methyl   4-tetrazol-1-yl-C.sub.6 H.sub.4                                                             389.2                                  (D = CONH.sub.2)                                                            148                                                                               pyrazole    CONH  methyl   4-(N-acetylpiperazin-                                                                       446.2                                                             1-yl)C.sub.6 H.sub.4                             149                                                                               pyrazole    CONH  methyl   4-(N-t-      504.3                                                             butoxycarbonylpiperazin-                                                       1-yl)C.sub.6 H.sub.4                             150                                                                               pyrazole    CONH  methyl   4-(piperazin-1-yl)C.sub.6 H.sub.4                                                           404.2                               151                                                                               pyrazole    CONH  CF.sub.3 4-cyclohexylphenyl                                                                          456.2                               152                                                                               pyrazole    CONH  methyl   4-(N-morpholino)-3-                                                                         439.2                                                             chloro-C.sub.6 H.sub.4                           153                                                                               pyrazole    CONH  CH.sub.3 S                                                                              2'-H.sub.2 NSO.sub.2 -biphenyl                                                              507.1                               154                                                                               pyrazole    CONH  CH.sub.3 SO                                                                             2'-H.sub.2 NSO.sub.2 -biphenyl                                                              523.1                               155                                                                               pyrazole    CONH  CH.sub.3 SO.sub.2                                                                       2'-H.sub.2 NSO.sub.2 -biphenyl                                                              539.1                               156                                                                               tetrazole   CH.sub.2                                                                             --       2'-CF.sub.3 -biphenyl                                                                       424.1                                  (D = CONH.sub.2)                                                            157                                                                               tetrazole   CH.sub.2                                                                             --       2'-H.sub.2 NSO.sub.2 -biphenyl                                                              435.1                                  (D = CONH.sub.2)                                                            158                                                                               pyrazole    CONH  methyl   4-cyclopentyloxyphenyl                                                                      404.2                               159                                                                               pyrazole    CONH  methyl   3-(pyrid-2-yl-NHCH.sub.2)                                                                   426.2                                                             C.sub.6 H.sub.4                                  160                                                                               pyrazole    CONH  methyl   4-(N-imidazolyl)phenyl                                                                      386.2                               161                                                                               pyrazole    CONH  CF.sub.3 4-(N-morpholino)-3-                                                                         493.1                                                             Cl--C.sub.6 H.sub.4                              162                                                                               pyrazole    CONH  methyl   4-(N-pyrrolidino-                                                                           451.2                                                             carbonyl)-3-Cl--C.sub.6 H.sub.4                  163                                                                               pyrazole    CONH  methyl   4-(N-morpholino-                                                                            433.2                                                             carbonyl)-3-Cl--C.sub.6 H.sub.4                  164                                                                               pyrazole    CONH  CF.sub.3 4-(N-imidazolyl)phenyl                                                                      423.2                                  D = --CN                                                                    165                                                                               pyrazole    CONH  CF.sub.3 4-(N-imidazolyl)phenyl                                                                      440.2                               166                                                                               pyrazole    CONH  CF.sub.3 4-(N-methyltetrazolon-                                                                      472.1                                                             1-yl)phenyl                                      167                                                                               pyrazole    COCH.sub.2                                                                           methyl   2'-H.sub.2 NSO.sub.2 -biphenyl                                                              433.2                                  (D = CONH.sub.2)                                                            168                                                                               pyrazole    CONH  methyl   4-N-pyrrolidino-                                                                            403.2                                                             methylphenyl                                     169                                                                               pyrazole    CONH  methyl   2'-H.sub.2 NSO.sub.2 -biphenyl                                                              448.1                                  (D = NH.sub.2)                                                              170                                                                               pyrazole    CONH  methyl   2'-H.sub.2 NSO.sub.2 -biphenyl                                                              448.1                                  (D = 2-NH.sub.2)                                                            171                                                                               pyrazole    CONH  methyl   2'-H.sub.2 NSO.sub.2 -biphenyl                                                              482.0                                  (D = NH.sub.)                                                                  (R = 4-Cl)                                                                  172                                                                               pyrazole    CONH  methyl   2'-H.sub.2 NSO.sub.2 -biphenyl                                                              466.0                                  (D = NH.sub.2)                                                                 (R = 4-F)                                                                   173                                                                               pyrazole    CONH  methyl   2'-H.sub.2 NSO.sub.2 -biphenyl                                                              478.1                                  (D = NH.sub.2)                                                                 (R = 4-OMe)                                                                 174                                                                               tetrazole   CONH  --       2'-H.sub.2 NSO.sub.2 -biphenyl                                                              470.0                                  (D = NH.sub.2)                                                                 (R = 4-Cl)                                                                  175                                                                               tetrazole   CONH  --       5-(2'-H.sub.2 NSO.sub.2 --C.sub.6 H.sub.4)-                                                 471.2                                  (D = NH.sub.2)             pyridin-2-yl                                        (R = 4-Cl)                                                                  176                                                                               tetrazole   CONH  --       2'-H.sub.2 NSO.sub.2 -biphenyl                                                              466.0                                  (D = NH.sub.2)                                                                 (R = 4-OMe)                                                                 177                                                                               pyrazole    CONH  methyl   5-(2'-H.sub.2 NSO.sub.2 --C.sub.6 H.sub.4)-                                                 463.3                                  (D = CH.sub.2 NH.sub.2)    pyridin-2-yl                                     178                                                                               pyrazole    CONH  methyl   2'-H.sub.2 NSO.sub.2 -biphenyl                                                              476                                    (D = CH.sub.2 NH.sub.2)                                                        (R = 4-CH.sub.3)                                                            179                                                                               pyrazole    CONH  methyl   2'-H.sub.2 NSO.sub.2 -biphenyl                                                              480                                    (D = CH.sub.2 NH.sub.2)                                                        (R = 4-F)                                                                   180                                                                               pyrazole    CONH  CF.sub.3 4-(N-pyrrolidino-                                                                           458.2                                  (D = CH.sub.2 NH.sub.2)    carbonyl)C.sub.6 H.sub.4                         181                                                                               pyrazole    CONH  methyl   2'-H.sub.2 NSO.sub.2 -biphenyl                                                              547.2                                  (D = *)                                                                     182                                                                               pyrazole    CONH  methyl   2'-t-Bu--NHSO.sub.2 -biphenyl                                                               603.2                                  (D = **)                                                                    183                                                                               pyrazole    CONH  methyl   2'-H.sub.2 NSO.sub.2 -biphenyl                                                              547.2                                  (D = **)                                                                    184                                                                               pyrazole    CONH  methyl   2'-H.sub.2 NSO.sub.2 -biphenyl                                                              631.2                                  (D = ***)                                                                   185                                                                               1-(pyrid-   CONH  methyl   3-F-2'-H.sub.2 NSO.sub.2 -biphenyl                                                          452                                    2-yl)-                                                                         pyrazole                                                                    186                                                                               1-(6-Br-    CONH  methyl   3-F-2'-H.sub.2 NSO.sub.2 -biphenyl                                                          530                                    pyrid-2-                                                                       yl)-                                                                           pyrazole                                                                    187                                                                               tetrazole   CONH  --       3-Cl-2'-H.sub.2 NSO.sub.2 -                                                                 504.0                                  (D = 3-NH.sub.2)           biphenyl                                            (R = 4-Cl)                                                                  188                                                                               tetrazole   CONH  --       4-(N-pyrrolidino-                                                                           430                                    (D = 3-NH.sub.2)           carbonyl)C.sub.6 H.sub.4                            (R = 4-Cl)                                                                  189                                                                               tetrazole   CONH  --       2'-H.sub.2 NSO.sub.2 -biphenyl                                                              450.2                                  (D = CH.sub.2 NH.sub.2)                                                     190                                                                               1,3,4-      CONH  H        3-F-2'-H.sub.2 NSO.sub.2 -biphenyl                                                          467.9                                  triazole                                                                       (D = CH.sub.2 NH.sub.2)                                                     191                                                                               imidazole-  CONH  --       2'-H.sub.2 NSO.sub.2 -biphenyl                                                              448.2                                  d                                                                              (D = CH.sub.2 NH.sub.2)                                                     192                                                                               imidazole-  CONH  --       2'-H.sub.3 CSO.sub.2 -biphenyl                                                              447                                    d                                                                              (D = CH.sub.2 NH.sub.2)                                                     193                                                                               imidazole-  CONH  --       2'-H.sub.2 NSO.sub.2 -biphenyl                                                              461.2                                  d                                                                           194                                                                               pyrazole    CONH  methyl   3-F-2'-H.sub.2 NSO.sub.2 -biphenyl                                                          494.1                                  (D =                                                                           CH.sub.2 NHCH.sub.3)                                                        195                                                                               pyrazole    CONH  methyl   3-F-2'-H.sub.3 CSO.sub.2 -biphenyl                                                          492.2                                  (D =                                                                           CH.sub.2 NHCH.sub.3)                                                        196                                                                               pyrazole    CONH  3-CF.sub.3                                                                              2'-H.sub.3 CSO.sub.2 -biphenyl                                                              545.1                                  (D = CH.sub.2 H.sub.2)                                                                           4-CH.sub.3                                                197                                                                               pyrazole    CONH  CF.sub.3 2-F-4-(N-pyrrolidino-                                                                       476.2                                  (D = CH.sub.2 NH.sub.2)    carbonyl)C.sub.6 H.sub.4                         198                                                                               pyrazole    CONH  CF.sub.3 3-F-4-(N-pyrrolidino-                                                                       476.2                                  (D = CH.sub.2 NH.sub.2)    carbonyl)C.sub.6 H.sub.4                         199                                                                               pyrazole    CONH  CF.sub.3 2'-H.sub.3 CSO.sub.2 -biphenyl                                                              515.1                                  (D = CH.sub.2 NH.sub.2)                                                     200                                                                               pyrazole    CONH  CF.sub.3 3-F-2'-H.sub.2 NSO.sub.2 -biphenyl                                                          534.1                                  (D = CH.sub.2 NH.sub.)                                                      201                                                                               pyrazole    CONH  CF.sub.3 5-(2'-H.sub.2 NSO.sub.2 --C.sub.6 H.sub.4)-                                                 520.1                                  (D = CH.sub.2 NH.sub.2)    [1,6-                                                                          dihydro]pyrimidin-2-yl                           202                                                                               pyrazole    CONH  CF.sub.3 5-(2'-H.sub.2 NSO.sub.2 --C.sub.6 H.sub.4)-                                                 518.1                                  (D = CH.sub.2 NH.sub.2)    pyrimidin-2-yl                                   203                                                                               pyrazole    CONH  CF.sub.3 2'-H.sub.2 NSO.sub.2 -biphenyl                                                              530.1                                  (D = CH(CH.sub.3)--NH.sub.2)                                                204                                                                               pyrazole    CONH  CF.sub.3 3-F-2'-H.sub.2 NSO.sub.2 -biphenyl                                                          616.9                                  (D = C(═NH)--N-                                                            morpholino)                                                                 205                                                                               pyrazole    CH(OH)CH.sub.2                                                                       CF.sub.3 2'-H.sub.2 NSO.sub.2 -biphenyl                                                              517.2                                  (D = CH.sub.2 NH.sub.2)                                                     206                                                                               pyrazole    CONH  CF.sub.3 3-F-2'-H.sub.3 CSO.sub.2 -biphenyl                                                          532.9                                  (D = CH.sub.2 NH.sub.2)                                                     207                                                                               pyrazole    CONH  CF.sub.3 5-(2'-H.sub.3 CSO.sub.2 --C.sub.6 H.sub.4)-                                                 517.1                                  (D = CH.sub.2 NH.sub.2)    pyrimidin-2-yl                                   208                                                                               pyrazole    CONH  CF.sub.3 3-F-2'-H.sub.2 NSO.sub.2 -biphenyl                                                          546                                 209                                                                               pyrazole    CONH  CF.sub.3 3-F-2'-H.sub.3 CSO.sub.2 -biphenyl                                                          547.1                               210                                                                               pyrazole    COCH.sub.2                                                                           CF.sub.3 2'-H.sub.2 NSO.sub.2 -biphenyl                                                              514.8                                  (D = CH.sub.2 NH.sub.2)                                                     211                                                                               pyrazole    CONH  CH.sub.2 SO.sub.2 --CH.sub.3                                                            2'-H.sub.2 NSO.sub.2 -biphenyl                                                              540.1                                  (D = CH.sub.2 NH.sub.2)                                                     212                                                                               pyrazole    CONH  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                          2'-H.sub.2 NSO.sub.2 -biphenyl                                                              568.1                               213                                                                               pyrazole    CONH  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                          3-F-2'-H.sub.3 CSO.sub.2 -biphenyl                                                          572.1                                  (D = CH.sub.2 NH.sub.2)                                                     214                                                                               pyrazole    CONH  methyl   5-(2'-H.sub.2 NSO.sub.2 --C.sub.6 H.sub.4)-                                                 535.1                                  (D = CH(═NH)NHCO.sub.2 CH.sub.3)                                                                      pyrimidin-2-yl                                   215                                                                               pyrazole    CONH  methyl   2'-H.sub.3 CSO.sub.2 -biphenyl                                                              461.2                                  (D = CH.sub.2 NH.sub.2)                                                     216                                                                               pyrazole    CONH  CF.sub.3 3-CH.sub.3 -2'-H.sub.3 CSO.sub.2 -                                                          530.2                                  (D = CH.sub.2 NH.sub.2)    biphenyl                                         217                                                                               1,2,3-      CONH  --       3-F-2'-H.sub.3 CSO.sub.2 -biphenyl                                                          466.1                                  triazole                                                                       (D = CH.sub.2 NH.sub.2)                                                     218                                                                               pyrazole    CONH  methyl   2'-H.sub.2 NSO.sub.2 -biphenyl                                                              476.2                                  (D = CH.sub.2 NH.sub.2)                                                        (R = 4-CH.sub.3)                                                            219                                                                               pyrazole    CONH  methyl   2'-H.sub.2 NSO.sub.2 -biphenyl                                                              480.2                                  (D = CH.sub.2 NH.sub.2)                                                        (R = 4-F)                                                                   220                                                                               pyrazole    CONH  methyl   2'-H.sub.2 NSO.sub.2 -biphenyl                                                              497.1                                  (D = CH.sub.2 NH.sub.2)                                                        (R = 4-Cl)                                                                  221                                                                               pyrazole    CONH  CF.sub.3 3-F-2'-H.sub.2 NSO.sub.2 -biphenyl                                                          551.9                                  (D = CH.sub.2 NH.sub.2)                                                        (R = 4-F)                                                                   222                                                                               pyrazole    CONH  methyl   3-F-2'-H.sub.2 NSO.sub.2 -biphenyl                                                          480                                    (D = CH.sub.2 NH.sub.2)                                                     223                                                                               pyrazole    CONH  methyl   3-F-2'-H.sub.3 CSO.sub.2 -biphenyl                                                          479                                    (D = CH.sub.2 NH.sub.2)                                                     224                                                                               pyrazole    CONH  methyl   3-F-4-(N-    423.2                                                             morpholino)phenyl                                225                                                                               pyrazole    CONH  methyl   3-F-4-(N-    410.2                                  (D = CH.sub.2 NH.sub.2)    morpholino)phenyl                                226                                                                               pyrazole    CONH  CF.sub.3 3-F-4-(2'-CH.sub.3 -                                                                        459.2                                  (D = CH.sub.2 NH.sub.2)    imidazol-1-yl)phenyl                             227                                                                               pyrazole    CH.sub.2 O                                                                           methyl   biphenyl     420                                    (D = CN)                                                                    228                                                                               pyrazole    CH.sub.2 O                                                                           methyl   biphenyl     437.2                               229                                                                               pyrazole    CH.sub.2 O                                                                           methyl   biphenyl     438.2                                  (D = CONH.sub.2)                                                            230                                                                               pyrazole    CONH  CF.sub.3 2-F-4-(N-    477.2                                                             morpholino)phenyl                                231                                                                               pyrazole    CONH  CF.sub.3 2-F-4-(N-    478.1                                  (D = CONH.sub.2)           morpholino)phenyl                                232                                                                               pyrazole    CONH  CF.sub.3 3-CF.sub.3 -4-(N-                                                                           514                                    (D = CH.sub.2 NH.sub.2)    morpholino)phenyl                                233                                                                               pyrazole    CONH  ethyl    3-F-2'-H.sub.2 NSO.sub.2 -biphenyl                                                          493.9                                  (D = CH.sub.2 NH.sub.2)                                                     234                                                                               pyrazole    CONH  ethyl    3-F-2'-H.sub.3 CSO.sub.2 -biphenyl                                                          493                                    (D = CH.sub. NH.sub.2)                                                      235                                                                               pyrazole    CONH  ethyl    2-F-4-(2'-H.sub.3 CSO.sub.2 -                                                               465.2                                  (D = CH.sub.2 NH.sub.2)    imidazolyl)phenyl                                236                                                                               1-(6-       CONH  methyl   2'-H.sub.2 NSO.sub.2 -biphenyl                                                              462.9                                  NH.sub.2 CH.sub.2 -                                                            pyrid-2-                                                                       yl)-                                                                           pyrazole                                                                    237                                                                               1-(6-       CONH  methyl   2'-t-BuHNSO.sub.2 -biphenyl                                                                 548.1                                  C(═NH.sub.2)NOH-                                                           pyrid-2-                                                                       yl)-                                                                           pyrazole                                                                    238                                                                               1-(6-AM-    CONH  methyl   2'-H.sub.2 NSO.sub.2 -biphenyl                                                              476.2                                  pyrid-2-                                                                       yl)-                                                                           pyrazole                                                                    239                                                                               1-(6-AM-    CONH  methyl   3-F-2'-H.sub.3 CSO.sub.2 -biphenyl                                                          493.9                                  pyrid-2-                                                                       yl)-                                                                           pyrazole                                                                    240                                                                               pyrazole    CONH  methyl   2-CH.sub.3 O-4-(N-                                                                          422.2                                  (D = CH.sub.2 NH.sub.2)    morpholino)phenyl                                241                                                                               pyrazole    CONH  methyl   4-(3'-CH.sub.3 -5'-oxo-3'-                                                                  403.1                                  (D = CH.sub.2 NH.sub.2)    pyrazolin-2'-yl)phenyl                           242                                                                               pyrazole    CONH  SCH.sub.3                                                                               2'-H.sub.3 CSO.sub.2 -biphenyl                                                              493                                    (D = CH.sub.2 NH.sub.2)                                                     243                                                                               pyrazole    CONH  CF.sub.3 2'-H.sub.3 CSO.sub.2 -biphenyl                                                              551                                    (D = CH.sub.2 NH.sub.2)                                                        (R = 4-F)                                                                   244                                                                               pyrazole    CONH  CO.sub.2 Et                                                                             3-F-2'-H.sub.3 CSO.sub.2 -biphenyl                                                          537.2                                  (D = CH.sub.2 NH.sub.2)                                                     245                                                                               pyrazole    CONH  COOH     3-F-2'-H.sub.3 CSO.sub.2 -biphenyl                                                          509.2                                  (D = CH.sub.2 NH.sub.2)                                                     246                                                                               pyrazole    CONH  CONH.sub.2                                                                              2-F-2'-H.sub.3 CSO.sub.2 -biphenyl                                                          537.2                                  (D = CH.sub.2 NH.sub.2)                                                     247                                                                               pyrazole    CONH  3-CF.sub.3                                                                              3-F-2'-H.sub.3 CSO.sub.2 -biphenyl                                                          605.2                                  (D = CH.sub.2 NH.sub.2)                                                                          4-CO.sub.2 Et                                             248                                                                               pyrazole    CONH  SCH.sub.3                                                                               3-F-2'-H.sub.3 CSO.sub.2 -biphenyl                                                          511                                    (D = CH.sub.2 NH.sub.2)                                                     249                                                                               pyrazole    CONH  SO.sub.2 CH.sub.3                                                                       3-F-2'-H.sub.3 CSO.sub.2 -biphenyl                                                          543                                    (D = CH.sub.2 NH.sub.2)                                                     250                                                                               pyrazole    CONH  CF.sub.3 4-((5-       442                                    (D = CH.sub.2 NH.sub.2)    CH.sub.3 ONHC(O))imidazol-1-                                                   yl)phenyl                                        251                                                                               pyrazole    CONH  CF.sub.3 4-(5-CH.sub.3 -1,2,3-                                                                       500                                    (D = CH.sub.2 NH.sub.2)    triazol-1-yl)phenyl                              __________________________________________________________________________      *D = Ethylcarboxyamidino.                                                      **D = 1"-imino1"-N-morpholino)methyl.                                          ***D = N((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxycarbonyl)amidino.        

The following tables contain representative examples of the present invention. Each entry in each table is intended to be paired with each formulae at the start of the table. For example, in Table 2, example 1 is intended to be paired with each of formulae a-nn and in Table 3, example 1 is intended to be paired with each of formulae a-nn.

The following groups are intended for group A in the following tables. ##STR68##

                  TABLE 2                                                          ______________________________________                                                           ##STR69##                                                    a                b                                                              ##STR70##                                                                                       ##STR71##                                                    c                d                                                              ##STR72##                                                                      ##STR73##                                                                     f                                                                               ##STR74##                                                                     g                                                                               ##STR75##                                                                     h                                                                               ##STR76##                                                                     i                                                                               ##STR77##                                                                     j                                                                               ##STR78##                                                                                       ##STR79##                                                    k                l                                                              ##STR80##                                                                                       ##STR81##                                                    m                n                                                              ##STR82##                                                                     o                                                                               ##STR83##                                                                     p                                                                               ##STR84##                                                                     q                                                                               ##STR85##                                                                     r                                                                               ##STR86##                                                                     s                                                                               ##STR87##                                                                     t                                                                               ##STR88##                                                                                       ##STR89##                                                    u                v                                                              ##STR90##                                                                                       ##STR91##                                                    w                x                                                              ##STR92##                                                                     y                                                                               ##STR93##                                                                     z                                                                               ##STR94##                                                                     aa                                                                              ##STR95##                                                                     bb                                                                              ##STR96##                                                                     cc                                                                              ##STR97##                                                                     dd                                                                              ##STR98##                                                                                       ##STR99##                                                    ee               ff                                                             ##STR100##                                                                                      ##STR101##                                                   gg               hh                                                             ##STR102##                                                                    ii                                                                              ##STR103##                                                                    jj                                                                              ##STR104##                                                                    kk                                                                              ##STR105##                                                                    ll                                                                              ##STR106##                                                                    mm                                                                              ##STR107##                                                                    nn                                                                              ##STR108##                                                                                      ##STR109##                                                   oo               pp                                                             ##STR110##                                                                                      ##STR111##                                                   qq               rr                                                             ##STR112##                                                                                      ##STR113##                                                   ss               tt                                                             ##STR114##                                                                                      ##STR115##                                                   uu               vv                                                            Ex # R.sup.1a  A           B                                                   ______________________________________                                         1    CH.sub.3       phenyl       2-(aminosulfonyl)phenyl                       2       CH.sub.3                                                                                   phenyl       2-(methylaminosulfonyl)phenyl                 3       CH.sub.3                                                                                   phenyl       1-pyrrolidinocarbonyl                         4       CH.sub.3                                                                                   phenyl       2-(methylsulfonyl)phenyl                      5       CH.sub.3                                                                                   phenyl       4-morpholino                                  6       CH.sub.3                                                                                   phenyl       2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl         7       CH.sub.3                                                                                   phenyl       4-morpholinocarbonyl                          8       CH.sub.3                                                                                   phenyl       2-methyl-1-imidazolyl                         9       CH.sub.3                                                                                   phenyl       5-methyl-1-imidazolyl                         10     CH.sub.3                                                                                    phenyl    2-methylsulfonyl-1-imidazolyl                    11     CH.sub.3                                                                                  2-pyridyl                                                                                    2-(aminosulfonyl)phenyl                        12     CH.sub.3                                                                                  2-pyridyl                                                                                 2-(methylaminosulfonyl)phenyl                     13     CH.sub.3                                                                                  2-pyridyl                                                                                     1-pyrrolidinocarbonyl                         14     CH.sub.3                                                                                  2-pyridyl                                                                                    2-(methylsulfonyl)phenyl                       15     CH.sub.3                                                                                  2-pyridyl                                                                                         4-morpholino                              16     CH.sub.3                                                                                  2-pyridyl                                                                                 2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl             17     CH.sub.3                                                                                  2-pyridyl                                                                                     4-morpholinocarbonyl                          18     CH.sub.3                                                                                  2-pyridyl                                                                                     2-methyl-1-imidazolyl                         19     CH.sub.3                                                                                  2-pyridyl                                                                                     5-methyl-1-imidazolyl                         20     CH.sub.3                                                                                  2-pyridyl                                                                                 2-methylsulfonyl-1-imidazolyl                     21     CH.sub.3                                                                                  3-pyridyl                                                                                    2-(aminosulfonyl)phenyl                        22     CH.sub.3                                                                                  3-pyridyl                                                                                 2-(methylaminosulfonyl)phenyl                     23     CH.sub.3                                                                                  3-pyridyl                                                                                     1-pyrrolidinocarbonyl                         24     CH.sub.3                                                                                  3-pyridyl                                                                                    2-(methylsulfonyl)phenyl                       25     CH.sub.3                                                                                  3-pyridyl                                                                                         4-morpholino                              26     CH.sub.3                                                                                   3-pyridyl                                                                                  2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl           27     CH.sub.3                                                                                   3-pyridyl                                                                                       4-morpholinocarbonyl                       28     CH.sub.3                                                                                   3-pyridyl                                                                                       2-methyl-1-imidazolyl                      29     CH.sub.3                                                                                   3-pyridyl                                                                                       5-methyl-1-imidazolyl                      30     CH.sub.3                                                                                   3-pyridyl                                                                                  2-methylsulfonyl-1-imidazolyl                   31     CH.sub.3                                                                                  2-pyrimidyl                                                                                   2-(aminosulfonyl)phenyl                       32     CH.sub.3                                                                                  2-pyrimidyl                                                                                2-(methylaminosulfonyl)phenyl                    33     CH.sub.3                                                                                  2-pyrimidyl                                                                                    1-pyrrolidinocarbonyl                        34     CH.sub.3                                                                                  2-pyrimidyl                                                                                   2-(methylsulfonyl)phenyl                      35     CH.sub.3                                                                                  2-pyrimidyl                                                                                        4-morpholino                             36     CH.sub.3                                                                                  2-pyrimidyl                                                                               2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl             37     CH.sub.3                                                                                  2-pyrimidyl                                                                                    4-morpholinocarbonyl                         38     CH.sub.3                                                                                  2-pyrimidyl                                                                                    2-methyl-1-imidazolyl                        39     CH.sub.3                                                                                  2-pyrimidyl                                                                                    5-methyl-1-imidazolyl                        40     CH.sub.3                                                                                  2-pyrimidyl                                                                               2-methylsulfonyl-1-imidazolyl                     41     CH.sub.3                                                                                  5-pyrimidyl                                                                                   2-(aminosulfonyl)phenyl                       42     CH.sub.3                                                                                  5-pyrimidyl                                                                               2-(methylaminosulfonyl)phenyl                     43     CH.sub.3                                                                                  5-pyrimidyl                                                                                    1-pyrrolidinocarbonyl                        44     CH.sub.3                                                                                  5-pyrimidyl                                                                                   2-(methylsulfonyl)phenyl                      45     CH.sub.3                                                                                  5-pyrimidyl                                                                                        4-morpholino                             46     CH.sub.3                                                                                  5-pyrimidyl                                                                               2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl             47     CH.sub.3                                                                                  5-pyrimidyl                                                                                    4-morpholinocarbonyl                         48     CH.sub.3                                                                                  5-pyrimidyl                                                                                    2-methyl-1-imidazolyl                        49     CH.sub.3                                                                                  5-pyrimidyl                                                                                    5-methyl-1-imidazolyl                        50     CH.sub.3                                                                                  5-pyrimidyl                                                                               2-methylsulfonyl-1-imidazolyl                     51     CH.sub.3                                                                                  2-Cl-phenyl                                                                                    2-(aminosulfonyl)phenyl                      52     CH.sub.3                                                                                  2-Cl-phenyl                                                                                2-(methylaminosulfonyl)phenyl                    53     CH.sub.3                                                                                  2-Cl-phenyl                                                                                     1-pyrrolidinocarbonyl                       54     CH.sub.3                                                                                  2-Cl-phenyl                                                                                    2-(methylsulfonyl)phenyl                     55     CH.sub.3                                                                                  2-Cl-phenyl                                                                                         4-morpholino                            56     CH.sub.3                                                                                  2-Cl-phenyl                                                                                2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl            57     CH.sub.3                                                                                  2-Cl-phenyl                                                                                     4-morpholinocarbonyl                        58     CH.sub.3                                                                                  2-Cl-phenyl                                                                                     2-methyl-1-imidazolyl                       59     CH.sub.3                                                                                  2-Cl-phenyl                                                                                     5-methyl-1-imidazolyl                       60     CH.sub.3                                                                                  2-Cl-phenyl                                                                                2-methylsulfonyl-1-imidazolyl                    61     CH.sub.3                                                                                  2-F-phenyl                                                                                      2-(aminosulfonyl)phenyl                     62     CH.sub.3                                                                                  2-F-phenyl                                                                                  2-(methylaminosulfonyl)phenyl                   63     CH.sub.3                                                                                  2-F-phenyl                                                                                       1-pyrrolidinocarbonyl                      64     CH.sub.3                                                                                  2-F-phenyl                                                                                      2-(methylsulfonyl)phenyl                    65     CH.sub.3                                                                                  2-F-phenyl                                                                                           4-morpholino                           66     CH.sub.3                                                                                  2-F-phenyl                                                                                  2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl           67     CH.sub.3                                                                                  2-F-phenyl                                                                                       4-morpholinocarbonyl                       68     CH.sub.3                                                                                  2-F-phenyl                                                                                       2-methyl-1-imidazolyl                      69     CH.sub.3                                                                                  2-F-phenyl                                                                                       5-methyl-1-imidazolyl                      70     CH.sub.3                                                                                  2-F-phenyl                                                                                  2-methylsulfonyl-1-imidazolyl                   71     CH.sub.3                                                                                2,6-diF-phenyl                                                                                 2-(aminosulfonyl)phenyl                        72     CH.sub.3                                                                                2,6-diF-phenyl                                                                             2-(methylaminosulfonyl)phenyl                      73     CH.sub.3                                                                                2,6-diF-phenyl                                                                                  1-pyrrolidinocarbonyl                         74     CH.sub.3                                                                                2,6-diF-phenyl                                                                               2-(methylsulfonyl)phenyl                         75     CH.sub.3                                                                                2,6-diF-phenyl                                                                                      4-morpholino                              76     CH.sub.3                                                                                2,6-diF-phenyl                                                                               2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl            77     CH.sub.3                                                                                2,6-diF-phenyl                                                                                 4-morpholinocarbonyl                           78     CH.sub.3                                                                                2,6-diF-phenyl                                                                                 2-methyl-1-imidazolyl                          79     CH.sub.3                                                                                2,6-diF-phenyl                                                                                 5-methyl-1-imidazolyl                          80     CH.sub.3                                                                                2,6-diF-phenyl                                                                            2-methylsulfonyl-1-imidazolyl                       81    CH.sub.2 CH.sub.3                                                                          phenyl            2-(aminosulfonyl)phenyl                    82    CH.sub.2 CH.sub.3                                                                          phenyl         2-(methylaminosulfonyl)phenyl                 83    CH.sub.2 CH.sub.3                                                                          phenyl             1-pyrrolidinocarbonyl                     84    CH.sub.2 CH.sub.3                                                                          phenyl            2-(methylsulfonyl)phenyl                   85    CH.sub.2 CH.sub.3                                                                          phenyl                  4-morpholino                         86    CH.sub.2 CH.sub.3                                                                          phenyl     2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl             87    CH.sub.2 CH.sub.3                                                                          phenyl             4-morpholinocarbonyl                      88    CH.sub.2 CH.sub.3                                                                          phenyl             2-methyl-1-imidazolyl                     89    CH.sub.2 CH.sub.3                                                                          phenyl             5-methyl-1-imidazolyl                     90    CH.sub.2 CH.sub.3                                                                          phenyl         2-methylsulfonyl-1-imidazolyl                 91    CH.sub.2 CH.sub.3                                                                         2-pyridyl        2-(aminosulfonyl)phenyl                      92    CH.sub.2 CH.sub.3                                                                         2-pyridyl    2-(methylaminosulfonyl)phenyl                    93    CH.sub.2 CH.sub.3                                                                         2-pyridyl         1-pyrrolidinocarbonyl                       94    CH.sub.2 CH.sub.3                                                                         2-pyridyl       2-(methylsulfonyl)phenyl                      95    CH.sub.2 CH.sub.3                                                                         2-pyridyl              4-morpholino                           96    CH.sub.2 CH.sub.3                                                                         2-pyridyl     2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl           97    CH.sub.2 CH.sub.3                                                                         2-pyridyl         4-morpholinocarbonyl                        98    CH.sub.2 CH.sub.3                                                                         2-pyridyl         2-methyl-1-imidazolyl                       99    CH.sub.2 CH.sub.3                                                                         2-pyridyl         5-methyl-1-imidazolyl                       100   CH.sub.2 CH.sub.3                                                                         2-pyridyl     2-methylsulfonyl-1-imidazolyl                   101   CH.sub.2 CH.sub.3                                                                         3-pyridyl        2-(aminosulfonyl)phenyl                      102   CH.sub.2 CH.sub.3                                                                         3-pyridyl    2-(methylaminosulfonyl)phenyl                    103   CH.sub.2 CH.sub.3                                                                         3-pyridyl         1-pyrrolidinocarbonyl                       104   CH.sub.2 CH.sub.3                                                                         3-pyridyl        2-(methylsulfonyl)phenyl                     105   CH.sub.2 CH.sub.3                                                                         3-pyridyl              4-morpholino                           106   CH.sub.2 CH.sub.3                                                                         3-pyridyl     2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl           107   CH.sub.2 CH.sub.3                                                                         3-pyridyl         4-morpholinocarbonyl                        108   CH.sub.2 CH.sub.3                                                                         3-pyridyl         2-methyl-1-imidazolyl                       109   CH.sub.2 CH.sub.3                                                                         3-pyridyl         5-methyl-1-imidazolyl                       110   CH.sub.2 CH.sub.3                                                                         3-pyridyl     2-methylsulfonyl-1-imidazolyl                   111   CH.sub.2 CH.sub.3                                                                        2-pyrimidyl                                                                                    2-(aminosulfonyl)phenyl                        112   CH.sub.2 CH.sub.3                                                                        2-pyrimidyl                                                                                 2-(methylaminosulfonyl)phenyl                     113   CH.sub.2 CH.sub.3                                                                        2-pyrimidyl                                                                                     1-pyrrolidinocarbonyl                         114   CH.sub.2 CH.sub.3                                                                        2-pyrimidyl                                                                                    2-(methylsulfonyl)phenyl                       115   CH.sub.2 CH.sub.3                                                                        2-pyrimidyl                                                                                          4-morpholino                             116   CH.sub.2 CH.sub.3                                                                        2-pyrimidyl                                                                                 2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl             117   CH.sub.2 CH.sub.3                                                                        2-pyrimidyl                                                                                    4-morpholinocarbonyl                           118   CH.sub.2 CH.sub.3                                                                        2-pyrimidyl                                                                                     2-methyl-1-imidazolyl                         119   CH.sub.2 CH.sub.3                                                                        2-pyrimidyl                                                                                     5-methyl-1-imidazolyl                         120   CH.sub.2 CH.sub.3                                                                        2-pyrimidyl                                                                                 2-methylsulfonyl-1-imidazolyl                     121   CH.sub.2 CH.sub.3                                                                        5-pyrimidyl                                                                                    2-(aminosulfonyl)phenyl                        122   CH.sub.2 CH.sub.3                                                                        5-pyrimidyl                                                                                 2-(methylaminosulfonyl)phenyl                     123   CH.sub.2 CH.sub.3                                                                        5-pyrimidyl                                                                                     1-pyrrolidinocarbonyl                         124   CH.sub.2 CH.sub.3                                                                        5-pyrimidyl                                                                                   2-(methylsulfonyl)phenyl                        125   CH.sub.2 CH.sub.3                                                                        5-pyrimidyl                                                                                          4-morpholino                             126   CH.sub.2 CH.sub.3                                                                        5-pyrimidyl                                                                                 2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl             127   CH.sub.2 CH.sub.3                                                                        5-pyrimidyl                                                                                    4-morpholinocarbonyl                           128   CH.sub.2 CH.sub.3                                                                        5-pyrimidyl                                                                                      2-methyl-1-imidazolyl                        129   CH.sub.2 CH.sub.3                                                                        5-pyrimidyl                                                                                      5-methyl-1-imidazolyl                        130   CH.sub.2 CH.sub.3                                                                        5-pyrimidyl                                                                                 2-methylsulfonyl-1-imidazolyl                     131   CH.sub.2 CH.sub.3                                                                        2-Cl-phenyl                                                                                    2-(aminosulfonyl)phenyl                        132   CH.sub.2 CH.sub.3                                                                        2-Cl-phenyl                                                                                  2-(methylaminosulfonyl)phenyl                    133   CH.sub.2 CH.sub.3                                                                        2-Cl-phenyl                                                                                     1-pyrrolidinocarbonyl                         134   CH.sub.2 CH.sub.3                                                                        2-Cl-phenyl                                                                                    2-(methylsulfonyl)phenyl                       135   CH.sub.2 CH.sub.3                                                                        2-Cl-phenyl                                                                                           4-morpholino                            136   CH.sub.2 CH.sub.3                                                                        2-Cl-phenyl                                                                                  2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl            137   CH.sub.2 CH.sub.3                                                                        2-Cl-phenyl                                                                                      4-morpholinocarbonyl                         138   CH.sub.2 CH.sub.3                                                                        2-Cl-phenyl                                                                                      2-methyl-1-imidazolyl                        139   CH.sub.2 CH.sub.3                                                                        2-Cl-phenyl                                                                                      5-methyl-1-imidazolyl                        140   CH.sub.2 CH.sub.3                                                                        2-Cl-phenyl                                                                                  2-methylsulfonyl-1-imidazolyl                    141   CH.sub.2 CH.sub.3                                                                        2-F-phenyl       2-(aminosulfonyl)phenyl                       142   CH.sub.2 CH.sub.3                                                                        2-F-phenyl     2-(methylaminosulfonyl)phenyl                   143   CH.sub.2 CH.sub.3                                                                        2-F-phenyl        1-pyrrolidinocarbonyl                        144   CH.sub.2 CH.sub.3                                                                        2-F-phenyl       2-(methylsulfonyl)phenyl                      145   CH.sub.2 CH.sub.3                                                                        2-F-phenyl              4-morpholino                           146   CH.sub.2 CH.sub.3                                                                        2-F-phenyl     2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl           147   CH.sub.2 CH.sub.3                                                                        2-F-phenyl         4-morpholinocarbonyl                        148   CH.sub.2 CH.sub.3                                                                        2-F-phenyl         2-methyl-1-imidazolyl                       149   CH.sub.2 CH.sub.3                                                                        2-F-phenyl         5-methyl-1-imidazolyl                       150   CH.sub.2 CH.sub.3                                                                        2-F-phenyl     2-methylsulfonyl-1-imidazolyl                   151   CH.sub.2 CH.sub.3                                                                       2,6-diF-phenyl                                                                                2-(aminosulfonyl)phenyl                          152   CH.sub.2 CH.sub.3                                                                       2,6-diF-phenyl                                                                              2-(methylaminosulfonyl)phenyl                      153   CH.sub.2 CH.sub.3                                                                       2,6-diF-phenyl                                                                                   1-pyrrolidinocarbonyl                         154   CH.sub.2 CH.sub.3                                                                       2,6-diF-phenyl                                                                                2-(methylsulfonyl)phenyl                         155   CH.sub.2 CH.sub.3                                                                       2,6-diF-phenyl                                                                                        4-morpholino                             156   CH.sub.2 CH.sub.3                                                                       2,6-diF-phenyl                                                                              2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               157   CH.sub.2 CH.sub.3                                                                       2,6-diF-phenyl                                                                                  4-morpholinocarbonyl                           158   CH.sub.2 CH.sub.3                                                                       2,6-diF-phenyl                                                                                  2-methyl-1-imidazolyl                          159   CH.sub.2 CH.sub.3                                                                       2,6-diF-phenyl                                                                                  5-methyl-1-imidazolyl                          160   CH.sub.2 CH.sub.3                                                                       2,6-diF-phenyl                                                                              2-methylsulfonyl-1-imidazolyl                      161    CF.sub.3                                                                                    phenyl          2-(aminosulfonyl)phenyl                    162    CF.sub.3                                                                                    phenyl        2-(methylaminosulfonyl)phenyl                163    CF.sub.3                                                                                    phenyl            1-pyrrolidinocarbonyl                    164    CF.sub.3                                                                                    phenyl          2-(methylsulfonyl)phenyl                   165    CF.sub.3                                                                                    phenyl                 4-morpholino                        166    CF.sub.3                                                                                    phenyl        2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl        167    CF.sub.3                                                                                    phenyl            4-morpholinocarbonyl                     168    CF.sub.3                                                                                    phenyl            2-methyl-1-imidazolyl                    169    CF.sub.3                                                                                    phenyl            5-methyl-1-imidazolyl                    170    CF.sub.3                                                                                     phenyl                                                                                    2-methylsulfonyl-1-imidazolyl                  171    CF.sub.3                                                                                    2-pyridyl                                                                                   2-(aminosulfonyl)phenyl                       172    CF.sub.3                                                                                    2-pyridyl                                                                               2-(methylaminosulfonyl)phenyl                     173    CF.sub.3                                                                                    2-pyridyl                                                                                    1-pyrrolidinocarbonyl                        174    CF.sub.3                                                                                    2-pyridyl                                                                                   2-(methylsulfonyl)phenyl                      175    CF.sub.3                                                                                    2-pyridyl                                                                                        4-morpholino                             176    CF.sub.3                                                                                    2-pyridyl                                                                               2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl             177    CF.sub.3                                                                                    2-pyridyl                                                                                    4-morpholinocarbonyl                         178    CF.sub.3                                                                                    2-pyridyl                                                                                    2-methyl-1-imidazolyl                        179    CF.sub.3                                                                                    2-pyridyl                                                                                    5-methyl-1-imidazolyl                        180    CF.sub.3                                                                                    2-pyridyl                                                                                2-methylsulfonyl-1-imidazolyl                    181    CF.sub.3                                                                                    3-pyridyl                                                                                   2-(aminosulfonyl)phenyl                       182    CF.sub.3                                                                                    3-pyridyl                                                                                2-(methylaminosulfonyl)phenyl                    183    CF.sub.3                                                                                    3-pyridyl                                                                                    1-pyrrolidinocarbonyl                        184    CF.sub.3                                                                                    3-pyridyl                                                                                   2-(methylsulfonyl)phenyl                      185    CF.sub.3                                                                                    3-pyridyl                                                                                        4-morpholino                             186    CF.sub.3                                                                                    3-pyridyl                                                                                2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl            187    CF.sub.3                                                                                    3-pyridyl                                                                                    4-morpholinocarbonyl                         188    CF.sub.3                                                                                    3-pyridyl                                                                                    2-methyl-1-imidazolyl                        189    CF.sub.3                                                                                    3-pyridyl                                                                                    5-methyl-1-imidazolyl                        190    CF.sub.3                                                                                    3-pyridyl                                                                                2-methylsulfonyl-1-imidazolyl                    191    CF.sub.3                                                                                   2-pyrimidyl                                                                                2-(aminosulfonyl)phenyl                         192    CF.sub.3                                                                                   2-pyrimidyl                                                                             2-(methylaminosulfonyl)phenyl                      193    CF.sub.3                                                                                   2-pyrimidyl                                                                                 1-pyrrolidinocarbonyl                          194    CF.sub.3                                                                                   2-pyrimidyl                                                                                2-(methylsulfonyl)phenyl                        195    CF.sub.3                                                                                   2-pyrimidyl                                                                                     4-morpholino                               196    CF.sub.3                                                                                   2-pyrimidyl                                                                             2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl              197    CF.sub.3                                                                                   2-pyrimidyl                                                                                 4-morpholinocarbonyl                           198    CF.sub.3                                                                                   2-pyrimidyl                                                                                 2-methyl-1-imidazolyl                          199    CF.sub.3                                                                                   2-pyrimidyl                                                                                 5-methyl-1-imidazolyl                          200    CF.sub.3                                                                                   2-pyrimidyl                                                                             2-methylsulfonyl-1-imidazolyl                      201    CF.sub.3                                                                                   5-pyrimidyl                                                                                2-(aminosulfonyl)phenyl                         202    CF.sub.3                                                                                   5-pyrimidyl                                                                             2-(methylaminosulfonyl)phenyl                      203    CF.sub.3                                                                                   5-pyrimidyl                                                                                 1-pyrrolidinocarbonyl                          204    CF.sub.3                                                                                   5-pyrimidyl                                                                                2-(methylsulfonyl)phenyl                        205    CF.sub.3                                                                                   5-pyrimidyl                                                                                     4-morpholino                               206    CF.sub.3                                                                                   5-pyrimidyl                                                                             2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl              207    CF.sub.3                                                                                   5-pyrimidyl                                                                                 4-morpholinocarbonyl                           208    CF.sub.3                                                                                   5-pyrimidyl                                                                                 2-methyl-1-imidazolyl                          209    CF.sub.3                                                                                   5-pyrimidyl                                                                                 5-methyl-1-imidazolyl                          210    CF.sub.3                                                                                   5-pyrimidyl                                                                             2-methylsulfonyl-1-imidazolyl                      211    CF.sub.3                                                                                   2-Cl-phenyl                                                                                 2-(aminosulfonyl)phenyl                        212    CF.sub.3                                                                                   2-Cl-phenyl                                                                              2-(methylaminosulfonyl)phenyl                     213    CF.sub.3                                                                                   2-Cl-phenyl                                                                                  1-pyrrolidinocarbonyl                         214    CF.sub.3                                                                                   2-Cl-phenyl                                                                                 2-(methylsulfonyl)phenyl                       215    CF.sub.3                                                                                   2-Cl-phenyl                                                                                      4-morpholino                              216    CF.sub.3                                                                                   2-Cl-phenyl                                                                              2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl             217    CF.sub.3                                                                                   2-Cl-phenyl                                                                                  4-morpholinocarbonyl                          218    CF.sub.3                                                                                  2-Cl-phenyl                                                                                    2-methyl-1-imidazolyl                        219    CF.sub.3                                                                                  2-Cl-phenyl                                                                                    5-methyl-1-imidazolyl                        220    CF.sub.3                                                                                  2-Cl-phenyl                                                                                2-methylsulfonyl-1-imidazolyl                    221    CF.sub.3                                                                                   2-F-phenyl                                                                                   2-(aminosulfonyl)phenyl                       222    CF.sub.3                                                                                   2-F-phenyl                                                                                2-(methylaminosulfonyl)phenyl                    223    CF.sub.3                                                                                   2-F-phenyl                                                                                    1-pyrrolidinocarbonyl                        224    CF.sub.3                                                                                   2-F-phenyl                                                                                   2-(methylsulfonyl)phenyl                      225    CF.sub.3                                                                                   2-F-phenyl                                                                                        4-morpholino                             226    CF.sub.3                                                                                   2-F-phenyl                                                                                2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl            227    CF.sub.3                                                                                   2-F-phenyl                                                                                    4-morpholinocarbonyl                         228    CF.sub.3                                                                                   2-F-phenyl                                                                                    2-methyl-1-imidazolyl                        229    CF.sub.3                                                                                   2-F-phenyl                                                                                    5-methyl-1-imidazolyl                        230    CF.sub.3                                                                                   2-F-phenyl                                                                                2-methylsulfonyl-1-imidazolyl                    231    CF.sub.3                                                                                 2,6-diF-phenyl                                                                              2-(aminosulfonyl)phenyl                          232    CF.sub.3                                                                                 2,6-diF-phenyl                                                                           2-(methylaminosulfonyl)phenyl                       233    CF.sub.3                                                                                 2,6-diF-phenyl                                                                               1-pyrrolidinocarbonyl                           234    CF.sub.3                                                                                 2,6-diF-phenyl                                                                              2-(methylsulfonyl)phenyl                         235    CF.sub.3                                                                                 2,6-diF-phenyl                                                                                    4-morpholino                               236    CF.sub.3                                                                                 2,6-diF-phenyl                                                                           2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl               237    CF.sub.3                                                                                 2,6-diF-phenyl                                                                               4-morpholinocarbonyl                            238    CF.sub.3                                                                                 2,6-diF-phenyl                                                                               2-methyl-1-imidazolyl                           239    CF.sub.3                                                                                 2,6-diF-phenyl                                                                               5-methyl-1-imidazolyl                           240    CF.sub.3                                                                                 2,6-diF-phenyl                                                                           2-methylsulfonyl-1-imidazolyl                       241    SCH.sub.3                                                                                  phenyl          2-(aminosulfonyl)phenyl                     242    SCH.sub.3                                                                                  phenyl       2-(methylaminosulfonyl)phenyl                  243    SCH.sub.3                                                                                  phenyl           1-pyrrolidinocarbonyl                      244    SCH.sub.3                                                                                  phenyl          2-(methylsulfonyl)phenyl                    245    SCH.sub.3                                                                                  phenyl               4-morpholino                           246    SCH.sub.3                                                                                  phenyl       2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl          247    SCH.sub.3                                                                                  phenyl           4-morpholinocarbonyl                       248    SCH.sub.3                                                                                  phenyl           2-methyl-1-imidazolyl                      249    SCH.sub.3                                                                                  phenyl           5-methyl-1-imidazolyl                      250    SCH.sub.3                                                                                  phenyl       2-methylsulfonyl-1-imidazolyl                  251    SCH.sub.3                                                                                2-pyridyl        2-(aminosulfonyl)phenyl                      252    SCH.sub.3                                                                                2-pyridyl     2-(methylaminosulfonyl)phenyl                   253    SCH.sub.3                                                                                2-pyridyl         1-pyrrolidinocarbonyl                       254    SCH.sub.3                                                                                2-pyridyl        2-(methylsulfonyl)phenyl                     255    SCH.sub.3                                                                                2-pyridyl             4-morpholino                            256    SCH.sub.3                                                                                2-pyridyl     2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl           257    SCH.sub.3                                                                                2-pyridyl         4-morpholinocarbonyl                        258    SCH.sub.3                                                                                2-pyridyl         2-methyl-1-imidazolyl                       259    SCH.sub.3                                                                                2-pyridyl         5-methyl-1-imidazolyl                       260    SCH.sub.3                                                                                2-pyridyl     2-methylsulfonyl-1-imidazolyl                   261    SCH.sub.3                                                                                3-pyridyl        2-(aminosulfonyl)phenyl                      262    SCH.sub.3                                                                                3-pyridyl     2-(methylaminosulfonyl)phenyl                   263    SCH.sub.3                                                                                3-pyridyl         1-pyrrolidinocarbonyl                       264    SCH.sub.3                                                                                3-pyridyl        2-(methylsulfonyl)phenyl                     265    SCH.sub.3                                                                                3-pyridyl             4-morpholino                            266     SCH.sub.3                                                                                3-pyridyl                                                                                  2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl            267     SCH.sub.3                                                                                3-pyridyl                                                                                      4-morpholinocarbonyl                         268     SCH.sub.3                                                                                3-pyridyl                                                                                      2-methyl-1-imidazolyl                        269     SCH.sub.3                                                                                3-pyridyl                                                                                      5-methyl-1-imidazolyl                        270     SCH.sub.3                                                                                3-pyridyl                                                                                  2-methylsulfonyl-1-imidazolyl                    271     SCH.sub.3                                                                               2-pyrimidyl                                                                                 2-(aminosulfonyl)phenyl                          272     SCH.sub.3                                                                               2-pyrimidyl                                                                               2-(methylaminosulfonyl)phenyl                      273     SCH.sub.3                                                                               2-pyrimidyl                                                                                   1-pyrrolidinocarbonyl                          274     SCH.sub.3                                                                               2-pyrimidyl                                                                                 2-(methylsulfonyl)phenyl                         275     SCH.sub.3                                                                               2-pyrimidyl                                                                                      4-morpholino                                276     SCH.sub.3                                                                               2-pyrimidyl                                                                               2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl              277     SCH.sub.3                                                                               2-pyrimidyl                                                                                   4-morpholinocarbonyl                           278     SCH.sub.3                                                                               2-pyrimidyl                                                                                   2-methyl-1-imidazolyl                          279     SCH.sub.3                                                                               2-pyrimidyl                                                                                   5-methyl-1-imidazolyl                          280     SCH.sub.3                                                                               2-pyrimidyl                                                                               2-methylsulfonyl-1-imidazolyl                      281     SCH.sub.3                                                                               5-pyrimidyl                                                                                 2-(aminosulfonyl)phenyl                          282     SCH.sub.3                                                                               5-pyrimidyl                                                                               2-(methylaminosulfonyl)phenyl                      283     SCH.sub.3                                                                               5-pyrimidyl                                                                                   1-pyrrolidinocarbonyl                          284     SCH.sub.3                                                                               5-pyrimidyl                                                                                 2-(methylsulfonyl)phenyl                         285     SCH.sub.3                                                                               5-pyrimidyl                                                                                        4-morpholino                              286     SCH.sub.3                                                                               5-pyrimidyl                                                                               2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl              287     SCH.sub.3                                                                               5-pyrimidyl                                                                                   4-morpholinocarbonyl                           288     SCH.sub.3                                                                               5-pyrimidyl                                                                                   2-methyl-1-imidazolyl                          289     SCH.sub.3                                                                               5-pyrimidyl                                                                                   5-methyl-1-imidazolyl                          290     SCH.sub.3                                                                               5-pyrimidyl                                                                               2-methylsulfonyl-1-imidazolyl                      291     SCH.sub.3                                                                               2-Cl-phenyl                                                                                  2-(aminosulfonyl)phenyl                         292     SCH.sub.3                                                                               2-Cl-phenyl                                                                                2-(methylaminosulfonyl)phenyl                     293     SCH.sub.3                                                                               2-Cl-phenyl                                                                                    1-pyrrolidinocarbonyl                         294     SCH.sub.3                                                                               2-Cl-phenyl                                                                                  2-(methylsulfonyl)phenyl                        295     SCH.sub.3                                                                               2-Cl-phenyl                                                                                         4-morpholino                             296     SCH.sub.3                                                                               2-Cl-phenyl                                                                                2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl             297     SCH.sub.3                                                                               2-Cl-phenyl                                                                                    4-morpholinocarbonyl                          298     SCH.sub.3                                                                               2-Cl-phenyl                                                                                    2-methyl-1-imidazolyl                         299     SCH.sub.3                                                                               2-Cl-phenyl                                                                                    5-methyl-1-imidazolyl                         300     SCH.sub.3                                                                               2-Cl-phenyl                                                                                2-methylsulfonyl-1-imidazolyl                     301     SCH.sub.3                                                                               2-F-phenyl                                                                                    2-(aminosulfonyl)phenyl                        302     SCH.sub.3                                                                               2-F-phenyl                                                                                  2-(methylaminosulfonyl)phenyl                    303     SCH.sub.3                                                                               2-F-phenyl                                                                                      1-pyrrolidinocarbonyl                        304     SCH.sub.3                                                                               2-F-phenyl                                                                                    2-(methylsulfonyl)phenyl                       305     SCH.sub.3                                                                               2-F-phenyl                                                                                           4-morpholino                            306     SCH.sub.3                                                                               2-F-phenyl                                                                                  2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl            307     SCH.sub.3                                                                               2-F-phenyl                                                                                      4-morpholinocarbonyl                         308     SCH.sub.3                                                                               2-F-phenyl                                                                                      2-methyl-1-imidazolyl                        309     SCH.sub.3                                                                               2-F-phenyl                                                                                      5-methyl-1-imidazolyl                        310     SCH.sub.3                                                                               2-F-phenyl                                                                                  2-methylsulfonyl-1-imidazolyl                    311     SCH.sub.3                                                                             2,6-diF-phenyl                                                                               2-(aminosulfonyl)phenyl                           312     SCH.sub.3                                                                             2,6-diF-phenyl                                                                              2-(methylaminosulfonyl)phenyl                      313     SCH.sub.3                                                                             2,6-diF-phenyl                                                                                  1-pyrrolidinocarbonyl                          314    SCH.sub.3                                                                                2,6-diF-phenyl                                                                             2-(methylsulfonyl)phenyl                          315    SCH.sub.3                                                                                2,6-diF-phenyl                                                                                   4-morpholino                                316    SCH.sub.3                                                                                2,6-diF-phenyl                                                                            2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl              317    SCH.sub.3                                                                                2,6-diF-phenyl                                                                              4-morpholinocarbonyl                             318    SCH.sub.3                                                                                2,6-diF-phenyl                                                                              2-methyl-1-imidazolyl                            319    SCH.sub.3                                                                                2,6-diF-phenyl                                                                              5-methyl-1-imidazolyl                            320    SCH.sub.3                                                                                2,6-diF-phenyl                                                                            2-methylsulfonyl-1-imidazolyl                      321    SOCH.sub.3                                                                                 phenyl          2-(aminosulfonyl)phenyl                     322    SOCH.sub.3                                                                                 phenyl       2-(methylaminosulfonyl)phenyl                  323    SOCH.sub.3                                                                                 phenyl           1-pyrrolidinocarbonyl                      324    SOCH.sub.3                                                                                 phenyl          2-(methylsulfonyl)phenyl                    325    SOCH.sub.3                                                                                 phenyl               4-morpholino                           326    SOCH.sub.3                                                                                 phenyl       2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl          327    SOCH.sub.3                                                                                 phenyl           4-morpholinocarbonyl                       328    SOCH.sub.3                                                                                 phenyl           2-methyl-1-imidazolyl                      329    SOCH.sub.3                                                                                 phenyl           5-methyl-1-imidazolyl                      330    SOCH.sub.3                                                                                 phenyl       2-methylsulfonyl-1-imidazolyl                  331    SOCH.sub.3                                                                                2-pyridyl                                                                                     2-(aminosulfonyl)phenyl                       332    SOCH.sub.3                                                                                2-pyridyl                                                                                 2-(methylaminosulfonyl)phenyl                     333    SOCH.sub.3                                                                                2-pyridyl                                                                                      1-pyrrolidinocarbonyl                        334    SOCH.sub.3                                                                                2-pyridyl                                                                                    2-(methylsulfonyl)phenyl                       335    SOCH.sub.3                                                                                2-pyridyl                                                                                          4-morpholino                             336    SOCH.sub.3                                                                                2-pyridyl                                                                                  2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl            337    SOCH.sub.3                                                                                2-pyridyl                                                                                      4-morpholinocarbonyl                         338    SOCH.sub.3                                                                                2-pyridyl                                                                                      2-methyl-1-imidazolyl                        339    SOCH.sub.3                                                                                2-pyridyl                                                                                      5-methyl-1-imidazolyl                        340    SOCH.sub.3                                                                                2-pyridyl                                                                                  2-methylsulfonyl-1-imidazolyl                    341    SOCH.sub.3                                                                                3-pyridyl                                                                                     2-(aminosulfonyl)phenyl                       342    SOCH.sub.3                                                                                3-pyridyl                                                                                  2-(methylaminosulfonyl)phenyl                    343    SOCH.sub.3                                                                                3-pyridyl                                                                                      1-pyrrolidinocarbonyl                        344    SOCH.sub.3                                                                                3-pyridyl                                                                                     2-(methylsulfonyl)phenyl                      345    SOCH.sub.3                                                                                3-pyridyl                                                                                          4-morpholino                             346    SOCH.sub.3                                                                                3-pyridyl                                                                                  2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl            347    SOCH.sub.3                                                                                3-pyridyl                                                                                      4-morpholinocarbonyl                         348    SOCH.sub.3                                                                                3-pyridyl                                                                                      2-methyl-1-imidazolyl                        349    SOCH.sub.3                                                                                3-pyridyl                                                                                      5-methyl-1-imidazolyl                        350    SOCH.sub.3                                                                                3-pyridyl                                                                                  2-methylsulfonyl-1-imidazolyl                    351    SOCH.sub.3                                                                               2-pyrimidyl                                                                                  2-(aminosulfonyl)phenyl                         352    SOCH.sub.3                                                                               2-pyrimidyl                                                                              2-(methylaminosulfonyl)phenyl                       353    SOCH.sub.3                                                                               2-pyrimidyl                                                                                    1-pyrrolidinocarbonyl                         354    SOCH.sub.3                                                                               2-pyrimidyl                                                                                 2-(methylsulfonyl)phenyl                         355    SOCH.sub.3                                                                               2-pyrimidyl                                                                                       4-morpholino                               356    SOCH.sub.3                                                                               2-pyrimidyl                                                                                2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl             357    SOCH.sub.3                                                                               2-pyrimidyl                                                                                   4-morpholinocarbonyl                           358    SOCH.sub.3                                                                               2-pyrimidyl                                                                                   2-methyl-1-imidazolyl                          359    SOCH.sub.3                                                                               2-pyrimidyl                                                                                   5-methyl-1-imidazolyl                          360    SOCH.sub.3                                                                               2-pyrimidyl                                                                               2-methylsulfonyl-1-imidazolyl                      361    SOCH.sub.3                                                                               5-pyrimidyl                                                                                  2-(aminosulfonyl)phenyl                         362    SOCH.sub.3                                                                               5-pyrimidyl                                                                                  2-(methylaminosulfonyl)phenyl                   363    SOCH.sub.3                                                                               5-pyrimidyl                                                                                   1-pyrrolidinocarbonyl                          364    SOCH.sub.3                                                                               5-pyrimidyl                                                                                  2-(methylsulfonyl)phenyl                        365    SOCH.sub.3                                                                               5-pyrimidyl                                                                                        4-morpholino                              366    SOCH.sub.3                                                                               5-pyrimidyl                                                                               2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl              367    SOCH.sub.3                                                                               5-pyrimidyl                                                                                   4-morpholinocarbonyl                           368    SOCH.sub.3                                                                               5-pyrimidyl                                                                                   2-methyl-1-imidazolyl                          369    SOCH.sub.3                                                                               5-pyrimidyl                                                                                   5-methyl-1-imidazolyl                          370    SOCH.sub.3                                                                               5-pyrimidyl                                                                               2-methylsulfonyl-1-imidazolyl                      371    SOCH.sub.3                                                                               2-Cl-phenyl                                                                                   2-(aminosulfonyl)phenyl                        372    SOCH.sub.3                                                                               2-Cl-phenyl                                                                                2-(methylaminosulfonyl)phenyl                     373    SOCH.sub.3                                                                               2-Cl-phenyl                                                                                    1-pyrrolidinocarbonyl                         374    SOCH.sub.3                                                                               2-Cl-phenyl                                                                                   2-(methylsulfonyl)phenyl                       375    SOCH.sub.3                                                                               2-Cl-phenyl                                                                                         4-morpholino                             376    SOCH.sub.3                                                                               2-Cl-phenyl                                                                                2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl             377    SOCH.sub.3                                                                               2-Cl-phenyl                                                                                    4-morpholinocarbonyl                          378    SOCH.sub.3                                                                               2-Cl-phenyl                                                                                    2-methyl-1-imidazolyl                         379    SOCH.sub.3                                                                               2-Cl-phenyl                                                                                    5-methyl-1-imidazolyl                         380    SOCH.sub.3                                                                               2-Cl-phenyl                                                                                2-methylsulfonyl-1-imidazolyl                     381    SOCH.sub.3                                                                               2-F-phenyl                                                                                     2-(aminosulfonyl)phenyl                       382    SOCH.sub.3                                                                               2-F-phenyl                                                                                 2-(methylaminosulfonyl)phenyl                     383    SOCH.sub.3                                                                               2-F-phenyl                                                                                     1-pyrrolidinocarbonyl                         384    SOCH.sub.3                                                                               2-F-phenyl                                                                                     2-(methylsulfonyl)phenyl                      385    SOCH.sub.3                                                                               2-F-phenyl                                                                                           4-morpholino                            386    SOCH.sub.3                                                                               2-F-phenyl                                                                                  2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl            387    SOCH.sub.3                                                                               2-F-phenyl                                                                                      4-morpholinocarbonyl                         388    SOCH.sub.3                                                                               2-F-phenyl                                                                                      2-methyl-1-imidazolyl                        389    SOCH.sub.3                                                                               2-F-phenyl                                                                                      5-methyl-1-imidazolyl                        390    SOCH.sub.3                                                                               2-F-phenyl                                                                                  2-methylsulfonyl-1-imidazolyl                    391    SOCH.sub.3                                                                             2,6-diF-phenyl                                                                                2-(aminosulfonyl)phenyl                          392    SOCH.sub.3                                                                             2,6-diF-phenyl                                                                             2-(methylaminosulfonyl)phenyl                       393    SOCH.sub.3                                                                             2,6-diF-phenyl                                                                                  1-pyrrolidinocarbonyl                          394    SOCH.sub.3                                                                             2,6-diF-phenyl                                                                                2-(methylsulfonyl)phenyl                         395    SOCH.sub.3                                                                             2,6-diF-phenyl                                                                                       4-morpholino                              396    SOCH.sub.3                                                                             2,6-diF-phenyl                                                                             2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl               397    SOCH.sub.3                                                                             2,6-diF-phenyl                                                                                 4-morpholinocarbonyl                            398    SOCH.sub.3                                                                             2,6-diF-phenyl                                                                                 2-methyl-1-imidazolyl                           399    SOCH.sub.3                                                                             2,6-diF-phenyl                                                                                 5-methyl-1-imidazolyl                           400    SOCH.sub.3                                                                             2,6-diF-phenyl                                                                             2-methylsulfonyl-1-imidazolyl                       401    SO.sub.2 CH.sub.3                                                                        phenyl             2-(aminosulfonyl)phenyl                    402    SO.sub.2 CH.sub.3                                                                        phenyl          2-(methylaminosulfonyl)phenyl                 403    SO.sub.2 CH.sub.3                                                                        phenyl              1-pyrrolidinocarbonyl                     404    SO.sub.2 CH.sub.3                                                                        phenyl             2-(methylsulfonyl)phenyl                   405    SO.sub.2 CH.sub.3                                                                        phenyl                   4-morpholino                         406    SO.sub.2 CH.sub.3                                                                        phenyl     2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl              407    SO.sub.2 CH.sub.3                                                                        phenyl              4-morpholinocarbonyl                      408    SO.sub.2 CH.sub.3                                                                        phenyl              2-methyl-1-imidazolyl                     409    SO.sub.2 CH.sub.3                                                                        phenyl              5-methyl-1-imidazolyl                     410   SO.sub.2 CH.sub.3                                                                          phenyl       2-methylsulfonyl-1-imidazolyl                   411   SO.sub.2 CH.sub.3                                                                        2-pyridyl        2-(aminosulfonyl)phenyl                       412   SO.sub.2 CH.sub.3                                                                        2-pyridyl     2-(methylaminosulfonyl)phenyl                    413   SO.sub.2 CH.sub.3                                                                        2-pyridyl         1-pyrrolidinocarbonyl                        414   SO.sub.2 CH.sub.3                                                                        2-pyridyl       2-(methylsulfonyl)phenyl                       415   SO.sub.2 CH.sub.3                                                                        2-pyridyl              4-morpholino                            416   SO.sub.2 CH.sub.3                                                                        2-pyridyl     2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl            417   SO.sub.2 CH.sub.3                                                                        2-pyridyl         4-morpholinocarbonyl                         418   SO.sub.2 CH.sub.3                                                                        2-pyridyl         2-methyl-1-imidazolyl                        419   SO.sub.2 CH.sub.3                                                                        2-pyridyl         5-methyl-1-imidazolyl                        420   SO.sub.2 CH.sub.3                                                                        2-pyridyl     2-methylsulfonyl-1-imidazolyl                    421   SO.sub.2 CH.sub.3                                                                        3-pyridyl       2-(aminosulfonyl)phenyl                        422   SO.sub.2 CH.sub.3                                                                        3-pyridyl    2-(methylaminosulfonyl)phenyl                     423   SO.sub.2 CH.sub.3                                                                        3-pyridyl         1-pyrrolidinocarbonyl                        424   SO.sub.2 CH.sub.3                                                                        3-pyridyl        2-(methylsulfonyl)phenyl                      425   SO.sub.2 CH.sub.3                                                                        3-pyridyl              4-morpholino                            426   SO.sub.2 CH.sub.3                                                                        3-pyridyl     2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl            427   SO.sub.2 CH.sub.3                                                                        3-pyridyl         4-morpholinocarbonyl                         428   SO.sub.2 CH.sub.3                                                                        3-pyridyl         2-methyl-1-imidazolyl                        429   SO.sub.2 CH.sub.3                                                                        3-pyridyl         5-methyl-1-imidazolyl                        430   SO.sub.2 CH.sub.3                                                                        3-pyridyl    2-methylsulfonyl-1-imidazolyl                     431   SO.sub.2 CH.sub.3                                                                       2-pyrimidyl     2-(aminosulfonyl)phenyl                         432   SO.sub.2 CH.sub.3                                                                       2-pyrimidyl  2-(methylaminosulfonyl)phenyl                      433   SO.sub.2 CH.sub.3                                                                       2-pyrimidyl      1-pyrrolidinocarbonyl                          434   SO.sub.2 CH.sub.3                                                                       2-pyrimidyl     2-(methylsulfonyl)phenyl                        435   SO.sub.2 CH.sub.3                                                                       2-pyrimidyl           4-morpholino                              436   SO.sub.2 CH.sub.3                                                                       2-pyrimidyl  2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl              437   SO.sub.2 CH.sub.3                                                                       2-pyrimidyl      4-morpholinocarbonyl                           438   SO.sub.2 CH.sub.3                                                                       2-pyrimidyl      2-methyl-1-imidazolyl                          439   SO.sub.2 CH.sub.3                                                                       2-pyrimidyl      5-methyl-1-imidazolyl                          440   SO.sub.2 CH.sub.3                                                                       2-pyrimidyl  2-methylsulfonyl-1-imidazolyl                      441   SO.sub.2 CH.sub.3                                                                       5-pyrimidyl     2-(aminosulfonyl)phenyl                         442   SO.sub.2 CH.sub.3                                                                       5-pyrimidyl  2-(methylaminosulfonyl)phenyl                      443   SO.sub.2 CH.sub.3                                                                       5-pyrimidyl      1-pyrrolidinocarbonyl                          444   SO.sub.2 CH.sub.3                                                                       5-pyrimidyl     2-(methylsulfonyl)phenyl                        445   SO.sub.2 CH.sub.3                                                                       5-pyrimidyl           4-morpholino                              446   SO.sub.2 CH.sub.3                                                                       5-pyrimidyl  2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl              447   SO.sub.2 CH.sub.3                                                                       5-pyrimidyl       4-morpholinocarbonyl                          448   SO.sub.2 CH.sub.3                                                                       5-pyrimidyl      2-methyl-1-imidazolyl                          449   SO.sub.2 CH.sub.3                                                                       5-pyrimidyl      5-methyl-1-imidazolyl                          450   SO.sub.2 CH.sub.3                                                                       5-pyrimidyl  2-methylsulfonyl-1-imidazolyl                      451   SO.sub.2 CH.sub.3                                                                       2-Cl-phenyl      2-(aminosulfonyl)phenyl                        452   SO.sub.2 CH.sub.3                                                                       2-Cl-phenyl   2-(methylaminosulfonyl)phenyl                     453   SO.sub.2 CH.sub.3                                                                       2-Cl-phenyl      1-pyrrolidinocarbonyl                          454   SO.sub.2 CH.sub.3                                                                       2-Cl-phenyl      2-(methylsulfonyl)phenyl                       455   SO.sub.2 CH.sub.3                                                                       2-Cl-phenyl            4-morpholino                             456   SO.sub.2 CH.sub.3                                                                       2-Cl-phenyl   2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl             457   SO.sub.2 CH.sub.3                                                                       2-Cl-phenyl      4-morpholinocarbonyl                           458   SO.sub.2 CH.sub.3                                                                         2-Cl-phenyl                                                                                   2-methyl-1-imidazolyl                          459   SO.sub.2 CH.sub.3                                                                         2-Cl-phenyl                                                                                   5-methyl-1-imidazolyl                          460   SO.sub.2 CH.sub.3                                                                         2-Cl-phenyl                                                                               2-methylsulfonyl-1-imidazolyl                      461   SO.sub.2 CH.sub.3                                                                         2-F-phenyl                                                                                    2-(aminosulfonyl)phenyl                        462   SO.sub.2 CH.sub.3                                                                         2-F-phenyl                                                                                2-(methylaminosulfonyl)phenyl                      463   SO.sub.2 CH.sub.3                                                                         2-F-phenyl                                                                                    1-pyrrolidinocarbonyl                          464   SO.sub.2 CH.sub.3                                                                         2-F-phenyl                                                                                    2-(methylsulfonyl)phenyl                       465   SO.sub.2 CH.sub.3                                                                         2-F-phenyl                                                                                          4-morpholino                             466   SO.sub.2 CH.sub.3                                                                         2-F-phenyl                                                                                 2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl             467   SO.sub.2 CH.sub.3                                                                         2-F-phenyl                                                                                     4-morpholinocarbonyl                          468   SO.sub.2 CH.sub.3                                                                         2-F-phenyl                                                                                     2-methyl-1-imidazolyl                         469   SO.sub.2 CH.sub.3                                                                         2-F-phenyl                                                                                     5-methyl-1-imidazolyl                         470   SO.sub.2 CH.sub.3                                                                         2-F-phenyl                                                                                 2-methylsulfonyl-1-imidazolyl                     471   SO.sub.2 CH.sub.3                                                                       2,6-diF-phenyl                                                                               2-(aminosulfonyl)phenyl                           472   SO.sub.2 CH.sub.3                                                                       2,6-diF-phenyl                                                                             2-(methylaminosulfonyl)phenyl                       473   SO.sub.2 CH.sub.3                                                                       2,6-diF-phenyl                                                                                1-pyrrolidinocarbonyl                            474   SO.sub.2 CH.sub.3                                                                       2,6-diF-phenyl                                                                               2-(methylsulfonyl)phenyl                          475   SO.sub.2 CH.sub.3                                                                       2,6-diF-phenyl                                                                                      4-morpholino                               476   SO.sub.2 CH.sub.3                                                                       2,6-diF-phenyl                                                                             2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl               477   SO.sub.2 CH.sub.3                                                                       2,6-diF-phenyl                                                                                4-morpholinocarbonyl                             478   SO.sub.2 CH.sub.3                                                                       2,6-diF-phenyl                                                                                 2-methyl-1-imidazolyl                           479   SO.sub.2 CH.sub.3                                                                       2,6-diF-phenyl                                                                                 5-methyl-1-imidazolyl                           480   SO.sub.2 CH.sub.3                                                                       2,6-diF-phenyl                                                                              2-methylsulfonyl-1-imidazolyl                      481   CH.sub.2 NH--                                                                               phenyl          2-(aminosulfonyl)phenyl                              SO.sub.2 CH.sub.3                                                     482   CH.sub.2 NH--                                                                               phenyl       2-(methylaminosulfonyl)phenyl                           SO.sub.2 CH.sub.3                                                     483   CH.sub.2 NH--                                                                               phenyl           1-pyrrolidinocarbonyl                               SO.sub.2 CH.sub.3                                                     484   CH.sub.2 NH--                                                                               phenyl          2-(methylsulfonyl)phenyl                             SO.sub.2 CH.sub.3                                                     485   CH.sub.2 NH--                                                                               phenyl                4-morpholino                                   SO.sub.2 CH.sub.3                                                     486   CH.sub.2 NH--                                                                               phenyl       2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl                   SO.sub.2 CH.sub.3                                                     487   CH.sub.2 NH--                                                                               phenyl           4-morpholinocarbonyl                                SO.sub.2 CH.sub.3                                                     488   CH.sub.2 NH--                                                                               phenyl           2-methyl-1-imidazolyl                               SO.sub.2 CH.sub.3                                                     489   CH.sub.2 NH--                                                                               phenyl           5-methyl-1-imidazolyl                               SO.sub.2 CH.sub.3                                                     490   CH.sub.2 NH--                                                                               phenyl       2-methylsulfonyl-1-imidazolyl                           SO.sub.2 CH.sub.3                                                     491   CH.sub.2 NH--                                                                              2-pyridyl                                                                                     2-(aminosulfonyl)phenyl                                SO.sub.2 CH.sub.3                                                     492   CH.sub.2 NH--                                                                              2-pyridyl                                                                                  2-(methylaminosulfonyl)phenyl                             SO.sub.2 CH.sub.3                                                     493  CH.sub.2 NH--                                                                                2-pyridyl                                                                                    1-pyrrolidinocarbonyl                                  SO.sub.2 CH.sub.3                                                     494  CH.sub.2 NH--                                                                                2-pyridyl                                                                                   2-(methylsulfonyl)phenyl                                SO.sub.2 CH.sub.3                                                     495  CH.sub.2 NH--                                                                                2-pyridyl                                                                                        4-morpholino                                       SO.sub.2 CH.sub.3                                                     496  CH.sub.2 NH--                                                                                2-pyridyl                                                                                2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl                      SO.sub.2 CH.sub.3                                                     497  CH.sub.2 NH--                                                                                2-pyridyl                                                                                    4-morpholinocarbonyl                                   SO.sub.2 CH.sub.3                                                     498  CH.sub.2 NH--                                                                                2-pyridyl                                                                                    2-methyl-1-imidazolyl                                  SO.sub.2 CH.sub.3                                                     499  CH.sub.2 NH--                                                                                2-pyridyl                                                                                    5-methyl-1-imidazolyl                                  SO.sub.2 CH.sub.3                                                     500  CH.sub.2 NH--                                                                                2-pyridyl                                                                                2-methylsulfonyl-1-imidazolyl                              SO.sub.2 CH.sub.3                                                     501  CH.sub.2 NH--                                                                                3-pyridyl                                                                                   2-(aminosulfonyl)phenyl                                 SO.sub.2 CH.sub.3                                                     502  CH.sub.2 NH--                                                                                3-pyridyl                                                                                2-(methylaminosulfonyl)phenyl                              SO.sub.2 CH.sub.3                                                     503  CH.sub.2 NH--                                                                                3-pyridyl                                                                                    1-pyrrolidinocarbonyl                                  SO.sub.2 CH.sub.3                                                     504  CH.sub.2 NH--                                                                                3-pyridyl                                                                                   2-(methylsulfonyl)phenyl                                SO.sub.2 CH.sub.3                                                     505  CH.sub.2 NH--                                                                                3-pyridyl                                                                                        4-morpholino                                       SO.sub.2 CH.sub.3                                                     506  CH.sub.2 NH--                                                                                3-pyridyl                                                                                2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl                      SO.sub.2 CH.sub.3                                                     507  CH.sub.2 NH--                                                                                3-pyridyl                                                                                    4-morpholinocarbonyl                                   SO.sub.2 CH.sub.3                                                     508  CH.sub.2 NH--                                                                                3-pyridyl                                                                                    2-methyl-1-imidazolyl                                  SO.sub.2 CH.sub.3                                                     509  CH.sub.2 NH--                                                                                3-pyridyl                                                                                    5-methyl-1-imidazolyl                                  SO.sub.2 CH.sub.3                                                     510  CH.sub.2 NH--                                                                                3-pyridyl                                                                                2-methylsulfonyl-1-imidazolyl                              SO.sub.2 CH.sub.3                                                     511  CH.sub.2 NH--                                                                               2-pyrimidyl                                                                                 2-(aminosulfonyl)phenyl                                  SO.sub.2 CH.sub.3                                                     512  CH.sub.2 NH--                                                                               2-pyrimidyl                                                                             2-(methylaminosulfonyl)phenyl                                SO.sub.2 CH.sub.3                                                     513  CH.sub.2 NH--                                                                               2-pyrimidyl                                                                                 1-pyrrolidinocarbonyl                                    SO.sub.2 CH.sub.3                                                     514  CH.sub.2 NH--                                                                               2-pyrimidyl                                                                                 2-(methylsulfonyl)phenyl                                 SO.sub.2 CH.sub.3                                                     515  CH.sub.2 NH--                                                                               2-pyrimidyl                                                                                     4-morpholino                                         SO.sub.2 CH.sub.3                                                     516  CH.sub.2 NH--                                                                               2-pyrimidyl                                                                              2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl                       SO.sub.2 CH.sub.3                                                     517   CH.sub.2 NH--                                                                            2-pyrimidyl                                                                                     4-morpholinocarbonyl                                   SO.sub.2 CH.sub.3                                                     518   CH.sub.2 NH--                                                                            2-pyrimidyl                                                                                    2-methyl-1-imidazolyl                                   SO.sub.2 CH.sub.3                                                     519   CH.sub.2 NH--                                                                            2-pyrimidyl                                                                                    5-methyl-1-imidazolyl                                   SO.sub.2 CH.sub.3                                                     520   CH.sub.2 NH--                                                                            2-pyrimidyl                                                                                2-methylsulfonyl-1-imidazolyl                               SO.sub.2 CH.sub.3                                                     521   CH.sub.2 NH--                                                                            5-pyrimidyl                                                                                    2-(aminosulfonyl)phenyl                                 SO.sub.2 CH.sub.3                                                     522   CH.sub.2 NH--                                                                            5-pyrimidyl                                                                                 2-(methylaminosulfonyl)phenyl                              SO.sub.2 CH.sub.3                                                     523   CH.sub.2 NH--                                                                            5-pyrimidyl                                                                                    1-pyrrolidinocarbonyl                                   SO.sub.2 CH.sub.3                                                     524   CH.sub.2 NH--                                                                            5-pyrimidyl                                                                                   2-(methylsulfonyl)phenyl                                 SO.sub.2 CH.sub.3                                                     525   CH.sub.2 NH--                                                                            5-pyrimidyl                                                                                         4-morpholino                                       SO.sub.2 CH.sub.3                                                     526   CH.sub.2 NH--                                                                            5-pyrimidyl                                                                                2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl                       SO.sub.2 CH.sub.3                                                     527   CH.sub.2 NH--                                                                            5-pyrimidyl                                                                                    4-morpholinocarbonyl                                    SO.sub.2 CH.sub.3                                                     528   CH.sub.2 NH--                                                                            5-pyrimidyl                                                                                    2-methyl-1-imidazolyl                                   SO.sub.2 CH.sub.3                                                     529   CH.sub.2 NH--                                                                            5-pyrimidyl                                                                                    5-methyl-1-imidazolyl                                   SO.sub.2 CH.sub.3                                                     530   CH.sub.2 NH--                                                                            5-pyrimidyl                                                                                2-methylsulfonyl-1-imidazolyl                               SO.sub.2 CH.sub.3                                                     531   CH.sub.2 NH--                                                                            2-Cl-phenyl                                                                                    2-(aminosulfonyl)phenyl                                 SO.sub.2 CH.sub.3                                                     532   CH.sub.2 NH--                                                                            2-Cl-phenyl                                                                                 2-(methylaminosulfonyl)phenyl                              SO.sub.2 CH.sub.3                                                     533   CH.sub.2 NH--                                                                            2-Cl-phenyl                                                                                     1-pyrrolidinocarbonyl                                  SO.sub.2 CH.sub.3                                                     534   CH.sub.2 NH--                                                                            2-Cl-phenyl                                                                                   2-(methylsulfonyl)phenyl                                 SO.sub.2 CH.sub.3                                                     535   CH.sub.2 NH--                                                                            2-Cl-phenyl                                                                                          4-morpholino                                      SO.sub.2 CH.sub.3                                                     536   CH.sub.2 NH--                                                                            2-Cl-phenyl                                                                                 2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl                      SO.sub.2 CH.sub.3                                                     537   CH.sub.2 NH--                                                                            2-Cl-phenyl                                                                                     4-morpholinocarbonyl                                   SO.sub.2 CH.sub.3                                                     538   CH.sub.2 NH--                                                                            2-Cl-phenyl                                                                                     2-methyl-1-imidazolyl                                  SO.sub.2 CH.sub.3                                                     539   CH.sub.2 NH--                                                                            2-Cl-phenyl                                                                                     5-methyl-1-imidazolyl                                  SO.sub.2 CH.sub.3                                                     540   CH.sub.2 NH--                                                                            2-Cl-phenyl                                                                                 2-methylsulfonyl-1-imidazolyl                              SO.sub.2 CH.sub.3                                                     541   CH.sub.2 NH--                                                                             2-F-phenyl                                                                                    2-(aminosulfonyl)phenyl                                 SO.sub.2 CH.sub.3                                                     542   CH.sub.2 NH--                                                                             2-F-phenyl                                                                                    2-(methylaminosulfonyl)phenyl                           SO.sub.2 CH.sub.3                                                     543   CH.sub.2 NH--                                                                             2-F-phenyl                                                                                     1-pyrrolidinocarbonyl                                  SO.sub.2 CH.sub.3                                                     544   CH.sub.2 NH--                                                                             2-F-phenyl                                                                                    2-(methylsulfonyl)phenyl                                SO.sub.2 CH.sub.3                                                     545   CH.sub.2 NH--                                                                             2-F-phenyl                                                                                         4-morpholino                                       SO.sub.2 CH.sub.3                                                     546   CH.sub.2 NH--                                                                             2-F-phenyl                                                                                 2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl                      SO.sub.2 CH.sub.3                                                     547   CH.sub.2 NH--                                                                             2-F-phenyl                                                                                     4-morpholinocarbonyl                                   SO.sub.2 CH.sub.3                                                     548   CH.sub.2 NH--                                                                             2-F-phenyl                                                                                     2-methyl-1-imidazolyl                                  SO.sub.2 CH.sub.3                                                     549   CH.sub.2 NH--                                                                             2-F-phenyl                                                                                     5-methyl-1-imidazolyl                                  SO.sub.2 CH.sub.3                                                     550   CH.sub.2 NH--                                                                             2-F-phenyl                                                                                 2-methylsulfonyl-1-imidazolyl                              SO.sub.2 CH.sub.3                                                     551   CH.sub.2 NH--                                                                             2,6-diF-phenyl                                                                              2-(aminosulfonyl)phenyl                                   SO.sub.2 CH.sub.3                                                     552   CH.sub.2 NH--                                                                             2,6-diF-phenyl                                                                            2-(methylaminosulfonyl)phenyl                               SO.sub.2 CH.sub.3                                                     553   CH.sub.2 NH--                                                                              2,6-diF-phenyl                                                                             1-pyrrolidinocarbonyl                                     SO.sub.2 CH.sub.3                                                     554   CH.sub.2 NH--                                                                              2,6-diF-phenyl                                                                             2-(methylsulfonyl)phenyl                                  SO.sub.2 CH.sub.3                                                     555   CH.sub.2 NH--                                                                              2,6-diF-phenyl                                                                                  4-morpholino                                         SO.sub.2 CH.sub.3                                                     556   CH.sub.2 NH--                                                                              2,6-diF-phenyl                                                                            2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl                      SO.sub.2 CH.sub.3                                                     557   CH.sub.2 NH--                                                                               2,6-diF-phenyl                                                                             4-morpholinocarbonyl                                     SO.sub.2 CH.sub.3                                                     558   CH.sub.2 NH--                                                                               2,6-diF-phenyl                                                                             2-methyl-1-imidazolyl                                    SO.sub.2 CH.sub.3                                                     559   CH.sub.2 NH--                                                                              2,6-diF-phenyl                                                                             5-methyl-1-imidazolyl                                     SO.sub.2 CH.sub.3                                                     560   CH.sub.2 NH--                                                                              2,6-diF-phenyl                                                                           2-methylsulfonyl-1-imidazolyl                               SO.sub.2 CH.sub.3                                                     561     Cl          phenyl        2-(aminosulfonyl)phenyl                      562     Cl          phenyl     2-(methylaminosulfonyl)phenyl                   563     Cl          phenyl         1-pyrrolidinocarbonyl                       564     Cl          phenyl        2-(methylsulfonyl)phenyl                     565     Cl          phenyl             4-morpholino                            566     Cl          phenyl     2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl           567     Cl          phenyl         4-morpholinocarbonyl                        568     Cl          phenyl         2-methyl-1-imidazolyl                       569     Cl          phenyl         5-methyl-1-imidazolyl                       570     Cl          phenyl      2-methylsulfonyl-1-imidazolyl                  571     Cl         2-pyridyl                                                                                     2-(aminosulfonyl)phenyl                      572     Cl         2-pyridyl                                                                                  2-(methylaminosulfonyl)phenyl                   573     Cl         2-pyridyl                                                                                      1-pyrrolidinocarbonyl                       574     Cl         2-pyridyl                                                                                     2-(methylsulfonyl)phenyl                     575     Cl         2-pyridyl                                                                                          4-morpholino                            576     Cl         2-pyridyl                                                                                  2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl           577     Cl         2-pyridyl                                                                                      4-morpholinocarbonyl                        578     Cl         2-pyridyl                                                                                      2-methyl-1-imidazolyl                       579     Cl         2-pyridyl                                                                                      5-methyl-1-imidazolyl                       580     Cl         2-pyridyl                                                                                  2-methylsulfonyl-1-imidazolyl                   581     Cl         3-pyridyl                                                                                     2-(aminosulfonyl)phenyl                      582     Cl         3-pyridyl                                                                                  2-(methylaminosulfonyl)phenyl                   583     Cl         3-pyridyl                                                                                      1-pyrrolidinocarbonyl                       584     Cl         3-pyridyl                                                                                     2-(methylsulfonyl)phenyl                     585     Cl         3-pyridyl                                                                                          4-morpholino                            586     Cl         3-pyridyl                                                                                  2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl           587     Cl         3-pyridyl                                                                                      4-morpholinocarbonyl                        588     Cl         3-pyridyl                                                                                      2-methyl-1-imidazolyl                       589     Cl         3-pyridyl                                                                                      5-methyl-1-imidazolyl                       590     Cl         3-pyridyl                                                                                  2-methylsulfonyl-1-imidazolyl                   591     Cl        2-pyrimidyl                                                                                  2-(aminosulfonyl)phenyl                        592     Cl        2-pyrimidyl                                                                               2-(methylaminosulfonyl)phenyl                     593     Cl        2-pyrimidyl                                                                                   1-pyrrolidinocarbonyl                         594     Cl        2-pyrimidyl                                                                                 2-(methylsulfonyl)phenyl                        595     Cl        2-pyrimidyl                                                                                       4-morpholino                              596     Cl        2-pyrimidyl                                                                               2-(1' -CF.sub.3 -tetrazol-2 -yl)phenyl            597     Cl        2-pyrimidyl                                                                                   4-morpholinocarbonyl                          598     Cl        2-pyrimidyl                                                                                   2-methyl-1-imidazolyl                         599     Cl        2-pyrimidyl                                                                                  5-methyl-1-imidazolyl                          600     Cl        2-pyrimidyl                                                                               2-methylsulfonyl-1-imidazolyl                     601     Cl        5-pyrimidyl                                                                                  2-(aminosulfonyl)phenyl                        602     Cl        5-pyrimidyl                                                                               2-(methylaminosulfonyl)phenyl                     603     Cl        5-pyrimidyl                                                                                   1-pyrrolidinocarbonyl                         604     Cl        5-pyrimidyl                                                                                  2-(methylsulfonyl)phenyl                       605     Cl        5-pyrimidyl                                                                                       4-morpholino                              606     Cl        5-pyrimidyl                                                                               2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl             607     Cl        5-pyrimidyl                                                                                   4-morpholinocarbonyl                          608     Cl        5-pyrimidyl                                                                                   2-methyl-1-imidazolyl                         609     Cl        5-pyrimidyl                                                                                   5-methyl-1-imidazolyl                         610     Cl        5-pyrimidyl                                                                               2-methylsulfonyl-1-imidazolyl                     611     Cl        2-Cl-phenyl                                                                                   2-(aminosulfonyl)phenyl                       612     Cl        2-Cl-phenyl                                                                                2-(methylaminosulfonyl)phenyl                    613     Cl        2-Cl-phenyl                                                                                    1-pyrrolidinocarbonyl                        614     Cl        2-Cl-phenyl                                                                                   2-(methylsulfonyl)phenyl                      615     Cl        2-Cl-phenyl                                                                                        4-morpholino                             616     Cl        2-Cl-phenyl                                                                                2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl            617     Cl        2-Cl-phenyl                                                                                   4-morpholinocarbonyl                          618     Cl        2-Cl-phenyl                                                                                    2-methyl-1-imidazolyl                        619     Cl        2-Cl-phenyl                                                                                    5-methyl-1-imidazolyl                        620     Cl        2-Cl-phenyl                                                                                2-methylsulfonyl-1-imidazolyl                    621     Cl        2-F-phenyl                                                                                     2-(aminosulfonyl)phenyl                      622     Cl        2-F-phenyl                                                                                  2-(methylaminosulfonyl)phenyl                   623     Cl        2-F-phenyl                                                                                      1-pyrrolidinocarbonyl                       624     Cl        2-F-phenyl                                                                                     2-(methylsulfonyl)phenyl                     625     Cl         2-F-phenyl                                                                                        4-morpholino                             626     Cl         2-F-phenyl                                                                                2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl            627     Cl         2-F-phenyl                                                                                    4-morpholinocarbonyl                         628     Cl         2-F-phenyl                                                                                    2-methyl-1-imidazolyl                        629     Cl         2-F-phenyl                                                                                    5-methyl-1-imidazolyl                        630     Cl         2-F-phenyl                                                                                2-methylsulfonyl-1-imidazolyl                    631     Cl       2,6-diF-phenyl                                                                             2-(aminosulfonyl)phenyl                           632     Cl       2,6-diF-phenyl                                                                           2-(methylaminosulfonyl)phenyl                       633     Cl       2,6-diF-phenyl                                                                               1-pyrrolidinocarbonyl                           634     Cl       2,6-diF-phenyl                                                                             2-(methylsulfonyl)phenyl                          635     Cl       2,6-diF-phenyl                                                                                    4-morpholino                               636     Cl       2,6-diF-phenyl                                                                            2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl              637     Cl       2,6-diF-phenyl                                                                                4-morpholinocarbonyl                           638     Cl       2,6-diF-phenyl                                                                                2-methyl-1-imidazolyl                          639     Cl       2,6-diF-phenyl                                                                                5-methyl-1-imidazolyl                          640     Cl       2,6-diF-phenyl                                                                           2-methylsulfonyl-1-imidazolyl                       641     F            phenyl                                                                                       2-(aminosulfonyl)phenyl                     642     F            phenyl                                                                                     2-(methylaminosulfonyl)phenyl                 643     F            phenyl                                                                                         1-pyrrolidinocarbonyl                     644     F            phenyl                                                                                       2-(methylsulfonyl)phenyl                    645     F            phenyl                                                                                             4-morpholino                          646     F            phenyl                                                                                     2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl          647     F            phenyl                                                                                         4-morpholinocarbonyl                      648     F            phenyl                                                                                         2-methyl-1-imidazolyl                     649     F            phenyl                                                                                         5-methyl-1-imidazolyl                     650     F            phenyl                                                                                     2-methylsulfonyl-1-imidazolyl                 651     F           2-pyridyl                                                                                   2-(aminosulfonyl)phenyl                       652     F           2-pyridyl                                                                                 2-(methylaminosulfonyl)phenyl                   653     F           2-pyridyl                                                                                     1-pyrrolidinocarbonyl                       654     F           2-pyridyl                                                                                   2-(methylsulfonyl)phenyl                      655     F           2-pyridyl                                                                                         4-morpholino                            656     F           2-pyridyl                                                                                 2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl           657     F           2-pyridyl                                                                                     4-morpholinocarbonyl                        658     F           2-pyridyl                                                                                     2-methyl-1-imidazolyl                       659     F           2-pyridyl                                                                                     5-methyl-1-imidazolyl                       660     F           2-pyridyl                                                                                 2-methylsulfonyl-1-imidazolyl                   661     F           3-pyridyl                                                                                   2-(aminosulfonyl)phenyl                       662     F           3-pyridyl                                                                                 2-(methylaminosulfonyl)phenyl                   663     F           3-pyridyl                                                                                     1-pyrrolidinocarbonyl                       664     F           3-pyridyl                                                                                   2-(methylsulfonyl)phenyl                      665     F           3-pyridyl                                                                                         4-morpholino                            666     F           3-pyridyl                                                                                 2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl           667     F           3-pyridyl                                                                                     4-morpholinocarbonyl                        668     F           3-pyridyl                                                                                     2-methyl-1-imidazolyl                       669     F           3-pyridyl                                                                                     5-methyl-1-imidazolyl                       670     F           3-pyridyl                                                                                 2-methylsulfonyl-1-imidazolyl                   671     F          2-pyrimidyl                                                                                2-(aminosulfonyl)phenyl                         672     F          2-pyrimidyl                                                                             2-(methylaminosulfonyl)phenyl                      673     F          2-pyrimidyl                                                                                  1-pyrrolidinocarbonyl                         674     F          2-pyrimidyl                                                                                2-(methylsulfonyl)phenyl                        675     F          2-pyrimidyl                                                                                      4-morpholino                              676     F          2-pyrimidyl                                                                              2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl             677     F          2-pyrimidyl                                                                                  4-morpholinocarbonyl                          678     F          2-pyrimidyl                                                                                  2-methyl-1-imidazolyl                         679     F          2-pyrimidyl                                                                                  5-methyl-1-imidazolyl                         680      F         2-pyrimidyl                                                                             2-methylsulfonyl-1-imidazolyl                      681      F         5-pyrimidyl                                                                                2-(aminosulfonyl)phenyl                         682      F         5-pyrimidyl                                                                             2-(methylaminosulfonyl)phenyl                      683      F         5-pyrimidyl                                                                                 1-pyrrolidinocarbonyl                          684      F         5-pyrimidyl                                                                                2-(methylsulfonyl)phenyl                        685      F         5-pyrimidyl                                                                                     4-morpholino                               686      F         5-pyrimidyl                                                                             2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl              687      F         5-pyrimidyl                                                                                 4-morpholinocarbonyl                           688      F         5-pyrimidyl                                                                                 2-methyl-1-imidazolyl                          689      F         5-pyrimidyl                                                                                 5-methyl-1-imidazolyl                          690      F         5-pyrimidyl                                                                            2-methylsulfonyl-1-imidazolyl                       691      F         2-Cl-phenyl                                                                                2-(aminosulfonyl)phenyl                         692      F         2-Cl-phenyl                                                                             2-(methylaminosulfonyl)phenyl                      693      F         2-Cl-phenyl                                                                                 1-pyrrolidinocarbonyl                          694      F         2-Cl-phenyl                                                                                2-(methylsulfonyl)phenyl                        695      F         2-Cl-phenyl                                                                                     4-morpholino                               696      F         2-Cl-phenyl                                                                             2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               697      F         2-Cl-phenyl                                                                                4-morpholinocarbonyl                            698      F         2-Cl-phenyl                                                                                 2-methyl-1-imidazolyl                          699      F         2-Cl-phenyl                                                                                 5-methyl-1-imidazolyl                          700      F         2-Cl-phenyl                                                                             2-methylsulfonyl-1-imidazolyl                      701      F         2-F-phenyl                                                                                  2-(aminosulfonyl)phenyl                        702      F         2-F-phenyl                                                                               2-(methylaminosulfonyl)phenyl                     703      F         2-F-phenyl                                                                                   1-pyrrolidinocarbonyl                         704      F         2-F-phenyl                                                                                  2-(methylsulfonyl)phenyl                       705      F         2-F-phenyl                                                                                       4-morpholino                              706      F         2-F-phenyl                                                                               2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl             707      F         2-F-phenyl                                                                                   4-morpholinocarbonyl                          708      F         2-F-phenyl                                                                                   2-methyl-1-imidazolyl                         709      F         2-F-phenyl                                                                                   5-methyl-1-imidazolyl                         710      F         2-F-phenyl                                                                               2-methylsulfonyl-1-imidazolyl                     711      F       2,6-diF-phenyl                                                                           2-(aminosulfonyl)phenyl                             712      F       2,6-diF-phenyl                                                                           2-(methylaminosulfonyl)phenyl                       713      F       2,6-diF-phenyl                                                                               1-pyrrolidinocarbonyl                           714      F       2,6-diF-phenyl                                                                             2-(methylsulfonyl)phenyl                          715      F       2,6-diF-phenyl                                                                                   4-morpholino                                716      F       2,6-diF-phenyl                                                                           2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                717      F       2,6-diF-phenyl                                                                               4-morpholinocarbonyl                            718      F       2,6-diF-phenyl                                                                              2-methyl-1-imidazolyl                            719      F       2,6-diF-phenyl                                                                              5-methyl-1-imidazolyl                            720      F       2,6-diF-phenyl                                                                           2-methylsulfonyl-1-imidazolyl                       721    CO.sub.2 CH.sub.3                                                                         phenyl          2-(aminosulfonyl)phenyl                      722    CO.sub.2 CH.sub.3                                                                         phenyl       2-(methylaminosulfonyl)phenyl                   723    CO.sub.2 CH.sub.3                                                                         phenyl           1-pyrrolidinocarbonyl                       724    CO.sub.2 CH.sub.3                                                                         phenyl          2-(methylsulfonyl)phenyl                     725    CO.sub.2 CH.sub.3                                                                         phenyl               4-morpholino                            726    CO.sub.2 CH.sub.3                                                                         phenyl      2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl            727    CO.sub.2 CH.sub.3                                                                         phenyl           4-morpholinocarbonyl                        728    CO.sub.2 CH.sub.3                                                                         phenyl           2-methyl-1-imidazolyl                       729    CO.sub.2 CH.sub.3                                                                         phenyl           5-methyl-1-imidazolyl                       730    CO.sub.2 CH.sub.3                                                                         phenyl       2-methylsulfonyl-1-imidazolyl                   731    CO.sub.2 CH.sub.3                                                                       2-pyridyl        2-(aminosulfonyl)phenyl                       732    CO.sub.2 CH.sub.3                                                                       2-pyridyl     2-(methylaminosulfonyl)phenyl                    733    CO.sub.2 CH.sub.3                                                                       2-pyridyl          1-pyrrolidinocarbonyl                       734    CO.sub.2 CH.sub.3                                                                       2-pyridyl         2-(methylsulfonyl)phenyl                     735    CO.sub.2 CH.sub.3                                                                       2-pyridyl               4-morpholino                           736    CO.sub.2 CH.sub.3                                                                       2-pyridyl      2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl            737    CO.sub.2 CH.sub.3                                                                       2-pyridyl          4-morpholinocarbonyl                        738    CO.sub.2 CH.sub.3                                                                       2-pyridyl          2-methyl-1-imidazolyl                       739    CO.sub.2 CH.sub.3                                                                       2-pyridyl         5-methyl-1-imidazolyl                        740    CO.sub.2 CH.sub.3                                                                       2-pyridyl      2-methylsulfonyl-1-imidazolyl                   741    CO.sub.2 CH.sub.3                                                                       3-pyridyl         2-(aminosulfonyl)phenyl                      742    CO.sub.2 CH.sub.3                                                                       3-pyridyl     2-(methylaminosulfonyl)phenyl                    743    CO.sub.2 CH.sub.3                                                                       3-pyridyl          1-pyrrolidinocarbonyl                       744    CO.sub.2 CH.sub.3                                                                       3-pyridyl         2-(methylsulfonyl)phenyl                     745    CO.sub.2 CH.sub.3                                                                       3-pyridyl               4-morpholino                           746    CO.sub.2 CH.sub.3                                                                       3-pyridyl      2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl           747    CO.sub.2 CH.sub.3                                                                       3-pyridyl          4-morpholinocarbonyl                        748    CO.sub.2 CH.sub.3                                                                       3-pyridyl          2-methyl-1-imidazolyl                       749    CO.sub.2 CH.sub.3                                                                       3-pyridyl          5-methyl-1-imidazolyl                       750    CO.sub.2 CH.sub.3                                                                       3-pyridyl      2-methylsulfonyl-1-imidazolyl                   751    CO.sub.2 CH.sub.3                                                                      2-pyrimidyl      2-(aminosulfonyl)phenyl                        752    CO.sub.2 CH.sub.3                                                                      2-pyrimidyl   2-(methylaminosulfonyl)phenyl                     753    CO.sub.2 CH.sub.3                                                                      2-pyrimidyl       1-pyrrolidinocarbonyl                         754    CO.sub.2 CH.sub.3                                                                      2-pyrimidyl      2-(methylsulfonyl)phenyl                       755    CO.sub.2 CH.sub.3                                                                      2-pyrimidyl            4-morpholino                             756    CO.sub.2 CH.sub.3                                                                      2-pyrimidyl   2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl             757    CO.sub.2 CH.sub.3                                                                      2-pyrimidyl      4-morpholinocarbonyl                           758    CO.sub.2 CH.sub.3                                                                      2-pyrimidyl       2-methyl-1-imidazolyl                         759    CO.sub.2 CH.sub.3                                                                      2-pyrimidyl       5-methyl-1-imidazolyl                         760    CO.sub.2 CH.sub.3                                                                      2-pyrimidyl   2-methylsulfonyl-1-imidazolyl                     761    CO.sub.2 CH.sub.3                                                                      5-pyrimidyl      2-(aminosulfonyl)phenyl                        762    CO.sub.2 CH.sub.3                                                                      5-pyrimidyl   2-(methylaminosulfonyl)phenyl                     763    CO.sub.2 CH.sub.3                                                                      5-pyrimidyl       1-pyrrolidinocarbonyl                         764    CO.sub.2 CH.sub.3                                                                      5-pyrimidyl      2-(methylsulfonyl)phenyl                       765    CO.sub.2 CH.sub.3                                                                      5-pyrimidyl            4-morpholino                             766    CO.sub.2 CH.sub.3                                                                      5-pyrimidyl   2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl              767    CO.sub.2 CH.sub.3                                                                      5-pyrimidyl       4-morpholinocarbonyl                          768    CO.sub.2 CH.sub.3                                                                      5-pyrimidyl       2-methyl-1-imidazolyl                         769    CO.sub.2 CH.sub.3                                                                      5-pyrimidyl       5-methyl-1-imidazolyl                         770    CO.sub.2 CH.sub.3                                                                      5-pyrimidyl   2-methylsulfonyl-1-imidazolyl                     771    CO.sub.2 CH.sub.3                                                                      2-Cl-phenyl       2-(aminosulfonyl)phenyl                       772    CO.sub.2 CH.sub.3                                                                      2-Cl-phenyl    2-(methylaminosulfonyl)phenyl                    773    CO.sub.2 CH.sub.3                                                                      2-Cl-phenyl        1-pyrrolidinocarbonyl                        774    CO.sub.2 CH.sub.3                                                                      2-Cl-phenyl       2-(methylsulfonyl)phenyl                      775    CO.sub.2 CH.sub.3                                                                      2-Cl-phenyl             4-morpholino                            776    CO.sub.2 CH.sub.3                                                                      2-Cl-phenyl    2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl             777    CO.sub.2 CH.sub.3                                                                      2-Cl-phenyl        4-morpholinocarbonyl                         778    CO.sub.2 CH.sub.3                                                                      2-Cl-phenyl        2-methyl-1-imidazolyl                        779    CO.sub.2 CH.sub.3                                                                      2-Cl-phenyl        5-methyl-1-imidazolyl                        780    CO.sub.2 CH.sub.3                                                                      2-Cl-phenyl    2-methylsulfonyl-1-imidazolyl                    781   CO.sub.2 CH.sub.3                                                                         2-F-phenyl                                                                                   2-(aminosulfonyl)phenyl                         782   CO.sub.2 CH.sub.3                                                                         2-F-phenyl                                                                                2-(methylaminosulfonyl)phenyl                      783   CO.sub.2 CH.sub.3                                                                         2-F-phenyl                                                                                     1-pyrrolidinocarbonyl                         784   CO.sub.2 CH.sub.3                                                                         2-F-phenyl                                                                                   2-(methylsulfonyl)phenyl                        785   CO.sub.2 CH.sub.3                                                                         2-F-phenyl                                                                                          4-morpholino                             786   CO.sub.2 CH.sub.3                                                                         2-F-phenyl                                                                                 2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl             787   CO.sub.2 CH.sub.3                                                                         2-F-phenyl                                                                                     4-morpholinocarbonyl                          788   CO.sub.2 CH.sub.3                                                                         2-F-phenyl                                                                                     2-methyl-1-imidazolyl                         789   CO.sub.2 CH.sub.3                                                                         2-F-phenyl                                                                                     5-methyl-1-imidazolyl                         790   CO.sub.2 CH.sub.3                                                                         2-F-phenyl                                                                                 2-methylsulfonyl-1-imidazolyl                     791   CO.sub.2 CH.sub.3                                                                       2,6-diF-phenyl                                                                              2-(aminosulfonyl)phenyl                            792   CO.sub.2 CH.sub.3                                                                       2,6-diF-phenyl                                                                             2-(methylaminosulfonyl)phenyl                       793   CO.sub.2 CH.sub.3                                                                       2,6-diF-phenyl                                                                                 1-pyrrolidinocarbonyl                           794   CO.sub.2 CH.sub.3                                                                       2,6-diF-phenyl                                                                              2-(methylsulfonyl)phenyl                           795   CO.sub.2 CH.sub.3                                                                       2,6-diF-phenyl                                                                                      4-morpholino                               796   CO.sub.2 CH.sub.3                                                                       2,6-diF-phenyl                                                                             2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl               797   CO.sub.2 CH.sub.3                                                                       2,6-diF-phenyl                                                                                4-morpholinocarbonyl                             798   CO.sub.2 CH.sub.3                                                                       2,6-diF-phenyl                                                                                2-methyl-1-imidazolyl                            799   CO.sub.2 CH.sub.3                                                                       2,6-diF-phenyl                                                                                5-methyl-1-imidazolyl                            800   CO.sub.2 CH.sub.3                                                                       2,6-diF-phenyl                                                                             2-methylsulfonyl-1-imidazolyl                       801  CH.sub.2 OCH.sub.3                                                                          phenyl          2-(aminosulfonyl)phenyl                      802  CH.sub.2 OCH.sub.3                                                                          phenyl        2-(methylaminosulfonyl)phenyl                  803  CH.sub.2 OCH.sub.3                                                                          phenyl            1-pyrrolidinocarbonyl                      804  CH.sub.2 OCH.sub.3                                                                          phenyl          2-(methylsulfonyl)phenyl                     805  CH.sub.2 OCH.sub.3                                                                          phenyl                 4-morpholino                          806  CH.sub.2 OCH.sub.3                                                                          phenyl        2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl          807  CH.sub.2 OCH.sub.3                                                                          phenyl            4-morpholinocarbonyl                       808  CH.sub.2 OCH.sub.3                                                                          phenyl            2-methyl-1-imidazolyl                      809  CH.sub.2 OCH.sub.3                                                                          phenyl            5-methyl-1-imidazolyl                      810  CH.sub.2 OCH.sub.3                                                                          phenyl        2-methylsulfonyl-1-imidazolyl                  811  CH.sub.2 OCH.sub.3                                                                         2-pyridyl      2-(aminosulfonyl)phenyl                        812  CH.sub.2 OCH.sub.3                                                                         2-pyridyl    2-(methylaminosulfonyl)phenyl                    813  CH.sub.2 OCH.sub.3                                                                         2-pyridyl        1-pyrrolidinocarbonyl                        814  CH.sub.2 OCH.sub.3                                                                         2-pyridyl      2-(methylsulfonyl)phenyl                       815  CH.sub.2 OCH.sub.3                                                                         2-pyridyl             4-morpholino                            816  CH.sub.2 OCH.sub.3                                                                         2-pyridyl    2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl            817  CH.sub.2 OCH.sub.3                                                                         2-pyridyl        4-morpholinocarbonyl                         818  CH.sub.2 OCH.sub.3                                                                         2-pyridyl        2-methyl-1-imidazolyl                        819  CH.sub.2 OCH.sub.3                                                                         2-pyridyl        5-methyl-1-imidazolyl                        820  CH.sub.2 OCH.sub.3                                                                         2-pyridyl    2-methylsulfonyl-1-imidazolyl                    821  CH.sub.2 OCH.sub.3                                                                         3-pyridyl      2-(aminosulfonyl)phenyl                        822  CH.sub.2 OCH.sub.3                                                                         3-pyridyl    2-(methylaminosulfonyl)phenyl                    823  CH.sub.2 OCH.sub.3                                                                         3-pyridyl        1-pyrrolidinocarbonyl                        824  CH.sub.2 OCH.sub.3                                                                         3-pyridyl      2-(methylsulfonyl)phenyl                       825  CH.sub.2 OCH.sub.3                                                                         3-pyridyl             4-morpholino                            826  CH.sub.2 OCH.sub.3                                                                         3-pyridyl    2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl            827  CH.sub.2 OCH.sub.3                                                                         3-pyridyl        4-morpholinocarbonyl                         828  CH.sub.2 OCH.sub.3                                                                         3-pyridyl        2-methyl-1-imidazolyl                        829  CH.sub.2 OCH.sub.3                                                                        3-pyridyl          5-methyl-1-imidazolyl                       830  CH.sub.2 OCH.sub.3                                                                        3-pyridyl     2-methylsulfonyl-1-imidazolyl                    831  CH.sub.2 OCH.sub.3                                                                        2-pyrimidyl                                                                                    2-(aminosulfonyl)phenyl                        832  CH.sub.2 OCH.sub.3                                                                        2-pyrimidyl                                                                                 2-(methylaminosulfonyl)phenyl                     833  CH.sub.2 OCH.sub.3                                                                        2-pyrimidyl                                                                                      1-pyrrolidinocarbonyl                        834  CH.sub.2 OCH.sub.3                                                                        2-pyrimidyl                                                                                  2-(methylsulfonyl)phenyl                         835  CH.sub.2 OCH.sub.3                                                                        2-pyrimidyl                                                                                          4-morpholino                             836  CH.sub.2 OCH.sub.3                                                                        2-pyrimidyl                                                                                 2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl             837  CH.sub.2 OCH.sub.3                                                                        2-pyrimidyl                                                                                     4-morpholinocarbonyl                          838  CH.sub.2 OCH.sub.3                                                                        2-pyrimidyl                                                                                      2-methyl-1-imidazolyl                        839  CH.sub.2 OCH.sub.3                                                                        2-pyrimidyl                                                                                     5-methyl-1-imidazolyl                         840  CH.sub.2 OCH.sub.3                                                                        2-pyrimidyl                                                                                 2-methylsulfonyl-1-imidazolyl                     841  CH.sub.2 OCH.sub.3                                                                        5-pyrimidyl                                                                                    2-(aminosulfonyl)phenyl                        842  CH.sub.2 OCH.sub.3                                                                        5-pyrimidyl                                                                                 2-(methylaminosulfonyl)phenyl                     843  CH.sub.2 OCH.sub.3                                                                        5-pyrimidyl                                                                                      1-pyrrolidinocarbonyl                        844  CH.sub.2 OCH.sub.3                                                                        5-pyrimidyl                                                                                    2-(methylsulfonyl)phenyl                       845  CH.sub.2 OCH.sub.3                                                                        5-pyrimidyl                                                                                         4-morpholino                              846  CH.sub.2 OCH.sub.3                                                                        5-pyrimidyl                                                                                 2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl             847  CH.sub.2 OCH.sub.3                                                                        5-pyrimidyl                                                                                      4-morpholinocarbonyl                         848  CH.sub.2 OCH.sub.3                                                                        5-pyrimidyl                                                                                     2-methyl-1-imidazolyl                         849  CH.sub.2 OCH.sub.3                                                                        5-pyrimidyl                                                                                      5-methyl-1-imidazolyl                        850  CH.sub.2 OCH.sub.3                                                                        5-pyrimidyl                                                                                 2-methylsulfonyl-1-imidazolyl                     851  CH.sub.2 OCH.sub.3                                                                        2-Cl-phenyl                                                                                    2-(aminosulfonyl)phenyl                        852  CH.sub.2 OCH.sub.3                                                                        2-Cl-phenyl                                                                                 2-(methylaminosulfonyl)phenyl                     853  CH.sub.2 OCH.sub.3                                                                        2-Cl-phenyl                                                                                      1-pyrrolidinocarbonyl                        854  CH.sub.2 OCH.sub.3                                                                        2-Cl-phenyl                                                                                    2-(methylsulfonyl)phenyl                       855  CH.sub.2 OCH.sub.3                                                                        2-Cl-phenyl                                                                                          4-morpholino                             856  CH.sub.2 OCH.sub.3                                                                        2-Cl-phenyl                                                                                 2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl             857  CH.sub.2 OCH.sub.3                                                                        2-Cl-phenyl                                                                                     4-morpholinocarbonyl                          858  CH.sub.2 OCH.sub.3                                                                        2-Cl-phenyl                                                                                      2-methyl-1-imidazolyl                        859  CH.sub.2 OCH.sub.3                                                                        2-Cl-phenyl                                                                                      5-methyl-1-imidazolyl                        860  CH.sub.2 OCH.sub.3                                                                        2-Cl-phenyl                                                                                 2-methylsulfonyl-1-imidazolyl                     861  CH.sub.2 OCH.sub.3                                                                        2-F-phenyl       2-(aminosulfonyl)phenyl                       862  CH.sub.2 OCH.sub.3                                                                        2-F-phenyl    2-(methylaminosulfonyl)phenyl                    863  CH.sub.2 OCH.sub.3                                                                        2-F-phenyl        1-pyrrolidinocarbonyl                        864  CH.sub.2 OCH.sub.3                                                                        2-F-phenyl       2-(methylsulfonyl)phenyl                      865  CH.sub.2 CCH.sub.3                                                                        2-F-phenyl             4-morpholino                            866  CH.sub.2 OCH.sub.3                                                                        2-F-phenyl    2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl            867  CH.sub.2 OCH.sub.3                                                                        2-F-phenyl         4-morpholinocarbonyl                        868  CH.sub.2 OCH.sub.3                                                                        2-F-phenyl         2-methyl-1-imidazolyl                       869  CH.sub.2 OCH.sub.3                                                                        2-F-phenyl         5-methyl-1-imidazolyl                       870  CH.sub.2 OCH.sub.3                                                                        2-F-phenyl    2-methylsulfonyl-1-imidazolyl                    871  CH.sub.2 OCH.sub.3                                                                       2,6-diF-phenyl                                                                               2-(aminosulfonyl)phenyl                           872  CH.sub.2 OCH.sub.3                                                                       2,6-diF-phenyl                                                                             2-(methylaminosulfonyl)phenyl                       873  CH.sub.2 OCH.sub.3                                                                       2,6-diF-phenyl                                                                                 1-pyrrolidinocarbonyl                           874  CH.sub.2 OCH.sub.3                                                                       2,6-diF-phenyl                                                                               2-(methylsulfonyl)phenyl                          875  CH.sub.2 OCH.sub.3                                                                       2,6-diF-phenyl                                                                                      4-morpholino                               876  CH.sub.2 OCH.sub.3                                                                       2,6-diF-phenyl                                                                              2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl              877  CH.sub.2 OCH.sub.3                                                                       2,6-diF-phenyl                                                                                4-morpholinocarbonyl                             878  CH.sub.2 OCH.sub.3                                                                       2,6-diF-phenyl                                                                                2-methyl-1-imidazolyl                            879  CH.sub.2 OCH.sub.3                                                                       2,6-diF-phenyl                                                                                5-methyl-1-imidazolyl                            880  CH.sub.2 OCH.sub.3                                                                       2,6-diF-phenyl                                                                             2-methylsulfonyl-1-imidazolyl                       881   CONH.sub.2                                                                                   phenyl       2-(aminosulfonyl)phenyl                       882   CONH.sub.2                                                                                   phenyl       2-(methylaminosulfonyl)phenyl                 883   CONH.sub.2                                                                                   phenyl        1-pyrrolidinocarbonyl                        884   CONH.sub.2                                                                                   phenyl       2-(methylsulfonyl)phenyl                      885   CONH.sub.2                                                                                   phenyl             4-morpholino                            886   CONH.sub.2                                                                                   phenyl     2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl            887   CONH.sub.2                                                                                   phenyl        4-morpholinocarbonyl                         888   CONH.sub.2                                                                                   phenyl        2-methyl-1-imidazolyl                        889   CONH.sub.2                                                                                   phenyl        5-methyl-1-imidazolyl                        890   CONH.sub.2                                                                                   phenyl     2-methylsulfonyl-1-imidazolyl                   891   CONH.sub.2                                                                                 2-pyridyl                                                                                    2-(aminosulfonyl)phenyl                        892   CONH.sub.2                                                                                 2-pyridyl                                                                                  2-(methylaminosulfonyl)phenyl                    893   CONH.sub.2                                                                                 2-pyridyl                                                                                     1-pyrrolidinocarbonyl                         894   CONH.sub.2                                                                                 2-pyridyl                                                                                    2-(methylsulfonyl)phenyl                       895   CONH.sub.2                                                                                 2-pyridyl                                                                                          4-morpholino                             896   CONH.sub.2                                                                                 2-pyridyl                                                                                  2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl             897   CONH.sub.2                                                                                 2-pyridyl                                                                                     4-morpholinocarbonyl                          898   CONH.sub.2                                                                                 2-pyridyl                                                                                     2-methyl-1-imidazolyl                         899   CONH.sub.2                                                                                 2-pyridyl                                                                                     5-methyl-1-imidazolyl                         900   CONH.sub.2                                                                                 2-pyridyl                                                                                  2-methylsulfonyl-1-imidazolyl                    901   CONH.sub.2                                                                                 3-pyridyl                                                                                    2-(aminosulfonyl)phenyl                        902   CONH.sub.2                                                                                 3-pyridyl                                                                                  2-(methylaminosulfonyl)phenyl                    903   CONH.sub.2                                                                                 3-pyridyl                                                                                     1-pyrrolidinocarbonyl                         904   CONH.sub.2                                                                                 3-pyridyl                                                                                    2-(methylsulfonyl)phenyl                       905   CONH.sub.2                                                                                 3-pyridyl                                                                                          4-morpholino                             906   CONH.sub.2                                                                                 3-pyridyl                                                                                  2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl            907   CONH.sub.2                                                                                 3-pyridyl                                                                                     4-morpholinocarbonyl                          908   CONH.sub.2                                                                                 3-pyridyl                                                                                     2-methyl-1-imidazolyl                         909   CONH.sub.2                                                                                 3-pyridyl                                                                                     5-methyl-1-imidazolyl                         910   CONH.sub.2                                                                                 3-pyridyl                                                                                  2-methylsulfonyl-1-imidazolyl                    911   CONH.sub.2                                                                                2-pyrimidyl                                                                                 2-(aminosulfonyl)phenyl                          912   CONH.sub.2                                                                                2-pyrimidyl                                                                                2-(methylaminosulfonyl)phenyl                     913   CONH.sub.2                                                                                2-pyrimidyl                                                                                  1-pyrrolidinocarbonyl                           914   CONH.sub.2                                                                                2-pyrimidyl                                                                                 2-(methylsulfonyl)phenyl                         915   CONH.sub.2                                                                                2-pyrimidyl                                                                                       4-morpholino                               916   CONH.sub.2                                                                                2-pyrimidyl                                                                               2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl              917   CONH.sub.2                                                                                2-pyrimidyl                                                                                  4-morpholinocarbonyl                            918   CONH.sub.2                                                                                2-pyrimidyl                                                                                  2-methyl-1-imidazolyl                           919   CONH.sub.2                                                                                2-pyrimidyl                                                                                  5-methyl-1-imidazolyl                           920   CONH.sub.2                                                                                2-pyrimidyl                                                                               2-methylsulfonyl-1-imidazolyl                      921   CONH.sub.2                                                                                5-pyrimidyl                                                                                 2-(aminosulfonyl)phenyl                          922   CONH.sub.2                                                                                5-pyrimidyl                                                                               2-(methylaminosulfonyl)phenyl                      923   CONH.sub.2                                                                                5-pyrimidyl                                                                                  1-pyrrolidinocarbonyl                           924   CONH.sub.2                                                                                5-pyrimidyl                                                                                 2-(methylsulfonyl)phenyl                         925   CONH.sub.2                                                                                 5-pyrimidyl                                                                                    4-morpholino                                 926   CONH.sub.2                                                                                 5-pyrimidyl                                                                             2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl               927   CONH.sub.2                                                                                 5-pyrimidyl                                                                                 4-morpholinocarbonyl                            928   CONH.sub.2                                                                                 5-pyrimidyl                                                                                2-methyl-1-imidazolyl                            929   CONH.sub.2                                                                                 5-pyrimidyl                                                                                5-methyl-1-imidazolyl                            930   CONH.sub.2                                                                                 5-pyrimidyl                                                                             2-methylsulfonyl-1-imidazolyl                       931   CONH.sub.2                                                                                 2-Cl-phenyl                                                                                2-(aminosulfonyl)phenyl                          932   CONH.sub.2                                                                                 2-Cl-phenyl                                                                             2-(methylaminosulfonyl)phenyl                       933   CONH.sub.2                                                                                 2-Cl-phenyl                                                                                1-pyrrolidinocarbonyl                            934   CONH.sub.2                                                                                 2-Cl-phenyl                                                                                2-(methylsulfonyl)phenyl                         935   CONH.sub.2                                                                                 2-Cl-phenyl                                                                                     4-morpholino                                936   CONH.sub.2                                                                                 2-Cl-phenyl                                                                             2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl               937   CONH.sub.2                                                                                 2-Cl-phenyl                                                                                 4-morpholinocarbonyl                            938   CONH.sub.2                                                                                 2-Cl-phenyl                                                                                 2-methyl-1-imidazolyl                           939   CONH.sub.2                                                                                 2-Cl-phenyl                                                                                 5-methyl-1-imidazolyl                           940   CONH.sub.2                                                                                 2-Cl-phenyl                                                                             2-methylsulfonyl-1-imidazolyl                       941   CONH.sub.2                                                                                 2-F-phenyl                                                                                  2-(aminosulfonyl)phenyl                         942   CONH.sub.2                                                                                 2-F-phenyl                                                                               2-(methylaminosulfonyl)phenyl                      943   CONH.sub.2                                                                                 2-F-phenyl                                                                                  1-pyrrolidinocarbonyl                           944   CONH.sub.2                                                                                 2-F-phenyl                                                                                  2-(methylsulfonyl)phenyl                        945   CONH.sub.2                                                                                 2-F-phenyl                                                                                       4-morpholino                               946   CONH.sub.2                                                                                 2-F-phenyl                                                                               2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl              947   CONH.sub.2                                                                                 2-F-phenyl                                                                                    4-morpholinocarbonyl                          948   CONH.sub.2                                                                                 2-F-phenyl                                                                                   2-methyl-1-imidazolyl                          949   CONH.sub.2                                                                                 2-F-phenyl                                                                                   5-methyl-1-imidazolyl                          950   CONH.sub.2                                                                                 2-F-phenyl                                                                               2-methylsulfonyl-1-imidazolyl                      951   CONH.sub.2                                                                               2,6-diF-phenyl                                                                             2-(aminosulfonyl)phenyl                            952   CONH.sub.2                                                                               2,6-diF-phenyl                                                                             2-(methylaminosulfonyl)phenyl                      953   CONH.sub.2                                                                               2,6-diF-phenyl                                                                               1-pyrrolidinocarbonyl                            954   CONH.sub.2                                                                               2,6-diF-phenyl                                                                             2-(methylsulfonyl)phenyl                           955   CONH.sub.2                                                                               2,6-diF-phenyl                                                                                   4-morpholino                                 956   CONH.sub.2                                                                               2,6-diF-phenyl                                                                             2-(1' -CF.sub.3 -tetrazol-2-yl)phenyl              957   CONH.sub.2                                                                               2,6-diF-phenyl                                                                               4-morpholinocarbonyl                             958   CONH.sub.2                                                                               2,6-diF-phenyl                                                                              2-methyl-1-imidazolyl                             959   CONH.sub.2                                                                               2,6-diF-phenyl                                                                               5-methyl-1-imidazolyl                            960   CONH.sub.2                                                                               2,6-diF-phenyl                                                                            2-methylsulfonyl-1-imidazolyl                       ______________________________________                                    

                  TABLE 3                                                          ______________________________________                                          ##STR116##                                                                                      ##STR117##                                                    ##STR118##                                                                                      ##STR119##                                                    ##STR120##                                                                                      ##STR121##                                                    ##STR122##                                                                     ##STR123##                                                                     ##STR124##                                                                     ##STR125##                                                                     ##STR126##                                                                                      ##STR127##                                                    ##STR128##                                                                                      ##STR129##                                                    ##STR130##                                                                     ##STR131##                                                                     ##STR132##                                                                     ##STR133##                                                                     ##STR134##                                                                     ##STR135##                                                                     ##STR136##                                                                                      ##STR137##                                                    ##STR138##                                                                                      ##STR139##                                                    ##STR140##                                                                     ##STR141##                                                                     ##STR142##                                                                     ##STR143##                                                                     ##STR144##                                                                     ##STR145##                                                                     ##STR146##                                                                                      ##STR147##                                                    ##STR148##                                                                                      ##STR149##                                                    ##STR150##                                                                     ##STR151##                                                                     ##STR152##                                                                     ##STR153##                                                                     ##STR154##                                                                     ##STR155##                                                                     ##STR156##                                                                                      ##STR157##                                                    ##STR158##                                                                                      ##STR159##                                                    ##STR160##                                                                                      ##STR161##                                                    ##STR162##                                                                                      ##STR163##                                                   Ex #     A            B                                                        ______________________________________                                         1              phenyl         2-(aminosulfonyl)phenyl                          2              phenyl      2-(methylaminosulfonyl)phenyl                       3              phenyl         1-pyrrolidinocarbonyl                            4              phenyl         2-(methylsulfonyl)phenyl                         5              phenyl              4-morpholino                                6              phenyl      2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                7              phenyl         4-morpholinocarbonyl                             8              phenyl         2-methyl-1-imidazolyl                            9              phenyl         5-methyl-1-imidazolyl                            10            phenyl       2-methylsulfonyl-1-imidazolyl                       11          2-pyridyl        2-(aminosulfonyl)phenyl                           12          2-pyridyl     2-(methylaminosulfonyl)phenyl                        13          2-pyridyl        1-pyrrolidinocarbonyl                             14          2-pyridyl        2-(methylsulfonyl)phenyl                          15          2-pyridyl        4-morpholino                                      16          2-pyridyl     2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                 17          2-pyridyl        4-morpholinocarbonyl                              18          2-pyridyl        2-methyl-1-imidazolyl                             19          2-pyridyl        5-methyl-1-imidazolyl                             20          2-pyridyl     2-methylsulfonyl-1-imidazolyl                        21          3-pyridyl        2-(aminosulfonyl)phenyl                           22          3-pyridyl     2-(methylaminosulfonyl)phenyl                        23          3-pyridyl       1-pyrrolidinocarbonyl                              24          3-pyridyl        2-(methylsulfonyl)phenyl                          25          3-pyridyl             4-morpholino                                 26          3-pyridyl     2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                 27          3-pyridyl        4-morpholinocarbonyl                              28          3-pyridyl        2-methyl-1-imidazolyl                             29          3-pyridyl        5-methyl-1-imidazolyl                             30          3-pyridyl     2-methylsulfonyl-1-imidazolyl                        31         2-pyrimidyl                                                                                    2-(aminosulfonyl)phenyl                             32         2-pyrimidyl                                                                                 2-(methylaminosulfonyl)phenyl                          33         2-pyrimidyl                                                                                     1-pyrrolidinocarbonyl                              34         2-pyrimidyl                                                                                     2-(methylsulfonyl)phenyl                           35         2-pyrimidyl                                                                                          4-morpholino                                  36         2-pyrimidyl                                                                                 2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                   37         2-pyrimidyl                                                                                     4-morpholinocarbonyl                               38         2-pyrimidyl                                                                                      2-methyl-1-imidazolyl                             39         2-pyrimidyl                                                                                      5-methyl-1-imidazolyl                             40         2-pyrimidyl                                                                                 2-methylsulfonyl-1-imidazolyl                          41         5-pyrimidyl                                                                                     2-(aminosulfonyl)phenyl                            42         5-pyrimidyl                                                                                 2-(methylaminosulfonyl)phenyl                          43         5-pyrimidyl                                                                                     1-pyrrolidinocarbonyl                              44         5-pyrimidyl                                                                                     2-(methylsulfonyl)phenyl                           45         5-pyrimidyl                                                                                          4-morpholino                                  46         5-pyrimidyl                                                                                 2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                   47         5-pyrimidyl                                                                                     4-morpholinocarbonyl                               48         5-pyrimidyl                                                                                      2-methyl-1-imidazolyl                             49         5-pyrimidyl                                                                                      5-methyl-1-imidazolyl                             50         5-pyrimidyl                                                                                 2-methylsulfonyl-1-imidazolyl                          51         2-Cl-phenyl                                                                                      2-(aminosulfonyl)phenyl                           52         2-Cl-phenyl                                                                                  2-(methylaminosulfonyl)phenyl                         53         2-Cl-phenyl                                                                                      1-pyrrolidinocarbonyl                             54         2-C1-phenyl                                                                                      2-(methylsulfonyl)phenyl                          55         2-Cl-phenyl                                                                                           4-morpholino                                 56         2-Cl-phenyl                                                                                  2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                  57         2-Cl-phenyl                                                                                     4-morpholinocarbonyl                               58         2-Cl-phenyl                                                                                       2-methyl-1-imidazolyl                            59         2-Cl-phenyl                                                                                       5-methyl-1-imidazolyl                            60         2-Cl-phenyl                                                                                  2-methylsulfonyl-1-imidazolyl                         61         2-F-phenyl         2-(aminosulfonyl)phenyl                          62         2-F-phenyl     2-(methylaminosulfonyl)phenyl                        63         2-F-phenyl          1-pyrrolidinocarbonyl                           64         2-F-phenyl         2-(methylsulfonyl)phenyl                         65         2-F-phenyl              4-morpholino                                66         2-F-phenyl     2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                 67         2-F-phenyl         4-morpholinocarbonyl                             68         2-F-phenyl          2-methyl-1-imidazolyl                           69         2-F-phenyl          5-methyl-1-imidazolyl                           70         2-F-phenyl     2-methylsulfonyl-1-imidazolyl                        71         2,6-diF-phenyl                                                                                2-(aminosulfonyl)phenyl                              72         2,6-diF-phenyl                                                                             2-(methylaminosulfonyl)phenyl                           73         2,6-diF-phenyl                                                                                 1-pyrrolidinocarbonyl                               74         2,6-diF-phenyl                                                                                2-(methylsulfonyl)phenyl                             75         2,6-diF-phenyl                                                                                      4-morpholino                                   76         2,6-diF-phenyl                                                                            2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                     77         2,6-diF-phenyl                                                                                 4-morpholinocarbonyl                                78         2,6-diF-phenyl                                                                                 2-methyl-1-imidazolyl                               79         2,6-diF-phenyl                                                                                 5-methyl-1-imidazolyl                               80         2,6-diF-phenyl                                                                            2-methylsulfonyl-1-imidazolyl                            ______________________________________                                    

                  TABLE 4                                                          ______________________________________                                          ##STR164##                                                                     ##STR165##                                                                     ##STR166##                                                                     ##STR167##                                                                     ##STR168##                                                                     ##STR169##                                                                     ##STR170##                                                                     ##STR171##                                                                     ##STR172##                                                                     ##STR173##                                                                     ##STR174##                                                                     ##STR175##                                                                     ##STR176##                                                                     ##STR177##                                                                     ##STR178##                                                                     ##STR179##                                                                     ##STR180##                                                                     ##STR181##                                                                     ##STR182##                                                                     ##STR183##                                                                     ##STR184##                                                                     ##STR185##                                                                     ##STR186##                                                                     ##STR187##                                                                     ##STR188##                                                                     ##STR189##                                                                     ##STR190##                                                                     ##STR191##                                                                     ##STR192##                                                                     ##STR193##                                                                     ##STR194##                                                                     ##STR195##                                                                     ##STR196##                                                                     ##STR197##                                                                     ##STR198##                                                                     ##STR199##                                                                     ##STR200##                                                                     ##STR201##                                                                     ##STR202##                                                                     ##STR203##                                                                     ##STR204##                                                                     ##STR205##                                                                     ##STR206##                                                                     ##STR207##                                                                     ##STR208##                                                                     ##STR209##                                                                     ##STR210##                                                                     ##STR211##                                                                    ______________________________________                                         Ex # R.sup.1a    A          B                                                  ______________________________________                                          1    CH.sub.3    phenyl     2-(aminosulfonyl)phenyl                           2    CH.sub.3    phenyl     2-(methylaminosulfonyl)-                                                       phenyl                                             3    CH.sub.3    phenyl     1-pyrrolidinocarbonyl                              4    CH.sub.3    phenyl     2-(methylsulfonyl)phenyl                           5    CH.sub.3    phenyl     4-morpholino                                       6    CH.sub.3    phenyl     2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               7    CH.sub.3    phenyl     4-morpholinocarbonyl                               8    CH.sub.3    phenyl     2-methyl-1-imidazolyl                              9    CH.sub.3    phenyl     5-methyl-1-imidazolyl                              10   CH.sub.3    phenyl     2-methylsulfonyl-1-imidazolyl                      11   CH.sub.3    2-pyridyl  2-(aminosulfonyl)phenyl                            12   CH.sub.3    2-pyridyl  2-(methylaminosulfonyl)-                                                       phenyl                                             13   CH.sub.3    2-pyridyl  1-pyrrolidinocarbonyl                              14   CH.sub.3    2-pyridyl  2-(methylsulfonyl)phenyl                           15   CH.sub.3    2-pyridyl  4-morpholino                                       16   CH.sub.3    2-pyridyl  2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               17   CH.sub.3    2-pyridyl  4-morpholinocarbonyl                               18   CH.sub.3    2-pyridyl  2-methyl-1-imidazolyl                              19   CH.sub.3    2-pyridyl  5-methyl-1-imidazolyl                              20   CH.sub.3    2-pyridyl  2-methylsulfonyl-1-imidazolyl                      21   CH.sub.3    3-pyridyl  2-(aminosulfonyl)phenyl                            22   CH.sub.3    3-pyridyl  2-(methylaminosulfonyl)-                                                       phenyl                                             23   CH.sub.3    3-pyridyl  1-pyrrolidinocarbonyl                              24   CH.sub.3    3-pyridyl  2-(methylsulfonyl)phenyl                           25   CH.sub.3    3-pyridyl  4-morpholino                                       26   CH.sub.3    3-pyridyl  2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               27   CH.sub.3    3-pyridyl  4-morpholinocarbonyl                               28   CH.sub.3    3-pyridyl  2-methyl-1-imidazolyl                              29   CH.sub.3    3-pyridyl  5-methyl-1-imidazolyl                              30   CH.sub.3    3-pyridyl  2-methylsulfonyl-1-imidazolyl                      31   CH.sub.3    2-pyrimidyl                                                                               2-(aminosulfonyl)phenyl                            32   CH.sub.3    2-pyrimidyl                                                                               2-(methylaminosulfonyl)-                                                       phenyl                                             33   CH.sub.3    2-pyrimidyl                                                                               1-pyrrolidinocarbonyl                              34   CH.sub.3    2-pyrimidyl                                                                               2-(methylsulfonyl)phenyl                           35   CH.sub.3    2-pyrimidyl                                                                               4-morpholino                                       36   CH.sub.3    2-pyrimidyl                                                                               2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               37   CH.sub.3    2-pyrimidyl                                                                               4-morpholinocarbonyl                               38   CH.sub.3    2-pyrimidyl                                                                               2-methyl-1-imidazolyl                              39   CH.sub.3    2-pyrimidyl                                                                               5-methyl-1-imidazolyl                              40   CH.sub.3    2-pyrimidyl                                                                               2-methylsulfonyl-1-imidazolyl                      41   CH.sub.3    5-pyrimidyl                                                                               2-(aminosulfonyl)phenyl                            42   CH.sub.3    5-pyrimidyl                                                                               2-(methylaminosulfonyl)-                                                       phenyl                                             43   CH.sub.3    5-pyrimidyl                                                                               1-pyrrolidinocarbonyl                              44   CH.sub.3    5-pyrimidyl                                                                               2-(methylsulfonyl)phenyl                           45   CH.sub.3    5-pyrimidyl                                                                               4-morpholino                                       46   CH.sub.3    5-pyrimidyl                                                                               2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               47   CH.sub.3    5-pyrimidyl                                                                               4-morpholinocarbonyl                               48   CH.sub.3    5-pyrimidyl                                                                               2-methyl-1-imidazolyl                              49   CH.sub.3    5-pyrimidyl                                                                               5-methyl-1-imidazolyl                              50   CH.sub.3    5-pyrimidyl                                                                               2-methylsulfonyl-1-imidazolyl                      51   CH.sub.3    2-Cl-phenyl                                                                               2-(aminosulfonyl)phenyl                            52   CH.sub.3    2-Cl-phenyl                                                                               2-(methylaminosulfonyl)-                                                       phenyl                                             53   CH.sub.3    2-Cl-phenyl                                                                               1-pyrrolidinocarbonyl                              54   CH.sub.3    2-Cl-phenyl                                                                               2-(methylsulfonyl)phenyl                           55   CH.sub.3    2-Cl-phenyl                                                                               4-morpholino                                       56   CH.sub.3    2-Cl-phenyl                                                                               2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               57   CH.sub.3    2-Cl-phenyl                                                                               4-morpholinocarbonyl                               58   CH.sub.3    2-Cl-phenyl                                                                               2-methyl-1-imidazolyl                              59   CH.sub.3    2-Cl-phenyl                                                                               5-methyl-1-imidazolyl                              60   CH.sub.3    2-Cl-phenyl                                                                               2-methylsulfonyl-1-imidazolyl                      61   CH.sub.3    2-F-phenyl 2-(aminosulfonyl)phenyl                            62   CH.sub.3    2-F-phenyl 2-(methylaminosulfonyl)-                                                       phenyl                                             63   CH.sub.3    2-F-phenyl 1-pyrrolidinocarbonyl                              64   CH.sub.3    2-F-phenyl 2-(methylsulfonyl)phenyl                           65   CH.sub.3    2-F-phenyl 4-morpholino                                       66   CH.sub.3    2-F-phenyl 2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               67   CH.sub.3    2-F-phenyl 4-morpholinocarbonyl                               68   CH.sub.3    2-F-phenyl 2-methyl-1-imidazolyl                              69   CH.sub.3    2-F-phenyl 5-methyl-1-imidazolyl                              70   CH.sub.3    2-F-phenyl 2-methylsulfonyl-1-imidazolyl                      71   CH.sub.3    2,6-diF-phenyl                                                                            2-(aminosulfonyl)phenyl                            72   CH.sub.3    2,6-diF-phenyl                                                                            2-(methylaminosulfonyl)-                                                       phenyl                                             73   CH.sub.3    2,6-diF-phenyl                                                                            1-pyrrolidinocarbonyl                              74   CH.sub.3    2,6-diF-phenyl                                                                            2-(methylsulfonyl)phenyl                           75   CH.sub.3    2,6-diF-phenyl                                                                            4-morpholino                                       76   CH.sub.3    2,6-diF-phenyl                                                                            2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               77   CH.sub.3    2,6-diF-phenyl                                                                            4-morpholinocarbonyl                               78   CH.sub.3    2,6-diF-phenyl                                                                            2-methyl-1-imidazolyl                              79   CH.sub.3    2,6-diF-phenyl                                                                            5-methyl-1-imidazolyl                              80   CH.sub.3    2,6-diF-phenyl                                                                            2-methylsulfonyl-1-imidazolyl                      81   CH.sub.2 CH.sub.3                                                                          phenyl     2-(aminosulfonyl)phenyl                            82   CH.sub.2 CH.sub.3                                                                          phenyl     2-(methylaminosulfonyl)-                                                       phenyl                                             83   CH.sub.2 CH.sub.3                                                                          phenyl     1-pyrrolidinocarbonyl                              84   CH.sub.2 CH.sub.3                                                                          phenyl     2-(methylsulfonyl)phenyl                           85   CH.sub.2 CH.sub.3                                                                          phenyl     4-morpholino                                       86   CH.sub.2 CH.sub.3                                                                          phenyl     2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               87   CH.sub.2 CH.sub.3                                                                          phenyl     4-morpholinocarbonyl                               88   CH.sub.2 CH.sub.3                                                                          phenyl     2-methyl-1-imidazolyl                              89   CH.sub.2 CH.sub.3                                                                          phenyl     5-methyl-1-imidazolyl                              90   CH.sub.2 CH.sub.3                                                                          phenyl     2-methylsulfonyl-1-imidazolyl                      91   CH.sub.2 CH.sub.3                                                                          2-pyridyl  2-(aminosulfonyl)phenyl                            92   CH.sub.2 CH.sub.3                                                                          2-pyridyl  2-(methylaminosulfonyl)-                                                       phenyl                                             93   CH.sub.2 CH.sub.3                                                                          2-pyridyl  1-pyrrolidinocarbonyl                              94   CH.sub.2 CH.sub.3                                                                          2-pyridyl  2-(methylsulfonyl)phenyl                           95   CH.sub.2 CH.sub.3                                                                          2-pyridyl  4-morpholino                                       96   CH.sub.2 CH.sub.3                                                                          2-pyridyl  2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               97   CH.sub.2 CH.sub.3                                                                          2-pyridyl  4-morpholinocarbonyl                               98   CH.sub.2 CH.sub.3                                                                          2-pyridyl  2-methyl-1-imidazolyl                              99   CH.sub.2 CH.sub.3                                                                          2-pyridyl  5-methyl-1-imidazolyl                              100  CH.sub.2 CH.sub.3                                                                          2-pyridyl  2-methylsulfonyl-1-imidazolyl                      101  CH.sub.2 CH.sub.3                                                                          3-pyridyl  2-(aminosulfonyl)phenyl                            102  CH.sub.2 CH.sub.3                                                                          3-pyridyl  2-(methylaminosulfonyl)-                                                       phenyl                                             103  CH.sub.2 CH.sub.3                                                                          3-pyridyl  1-pyrrolidinocarbonyl                              104  CH.sub.2 CH.sub.3                                                                          3-pyridyl  2-(methylsulfonyl)phenyl                           105  CH.sub.2 CH.sub.3                                                                          3-pyridyl  4-morpholino                                       106  CH.sub.2 CH.sub.3                                                                          3-pyridyl  2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               107  CH.sub.2 CH.sub.3                                                                          3-pyridyl  4-morpholinocarbonyl                               108  CH.sub.2 CH.sub.3                                                                          3-pyridyl  2-methyl-1-imidazolyl                              109  CH.sub.2 CH.sub.3                                                                          3-pyridyl  5-methyl-1-imidazolyl                              110  CH.sub.2 CH.sub.3                                                                          3-pyridyl  2-methylsulfonyl-1-imidazolyl                      111  CH.sub.2 CH.sub.3                                                                          2-pyrimidyl                                                                               2-(aminosulfonyl)phenyl                            112  CH.sub.2 CH.sub.3                                                                          2-pyrimidyl                                                                               2-(methylaminosulfonyl)-                                                       phenyl                                             113  CH.sub.2 CH.sub.3                                                                          2-pyrimidyl                                                                               1-pyrrolidinocarbonyl                              114  CH.sub.2 CH.sub.3                                                                          2-pyrimidyl                                                                               2-(methylsulfonyl)phenyl                           115  CH.sub.2 CH.sub.3                                                                          2-pyrimidyl                                                                               4-morpholino                                       116  CH.sub.2 CH.sub.3                                                                          2-pyrimidyl                                                                               2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               117  CH.sub.2 CH.sub.3                                                                          2-pyrimidyl                                                                               4-morpholinocarbonyl                               118  CH.sub.2 CH.sub.3                                                                          2-pyrimidyl                                                                               2-methyl-1-imidazolyl                              119  CH.sub.2 CH.sub.3                                                                          2-pyrimidyl                                                                               5-methyl-1-imidazolyl                              120  CH.sub.2 CH.sub.3                                                                          2-pyrimidyl                                                                               2-methylsulfonyl-1-imidazolyl                      121  CH.sub.2 CH.sub.3                                                                          5-pyrimidyl                                                                               2-(aminosulfonyl)phenyl                            122  CH.sub.2 CH.sub.3                                                                          5-pyrimidyl                                                                               2-(methylaminosulfonyl)-                                                       phenyl                                             123  CH.sub.2 CH.sub.3                                                                          5-pyrimidyl                                                                               1-pyrrolidinocarbonyl                              124  CH.sub.2 CH.sub.3                                                                          5-pyrimidyl                                                                               2-(methylsulfonyl)phenyl                           125  CH.sub.2 CH.sub.3                                                                          5-pyrimidyl                                                                               4-morpholino                                       126  CH.sub.2 CH.sub.3                                                                          5-pyrimidyl                                                                               2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               127  CH.sub.2 CH.sub.3                                                                          5-pyrimidyl                                                                               4-morpholinocarbonyl                               128  CH.sub.2 CH.sub.3                                                                          5-pyrimidyl                                                                               2-methyl-1-imidazolyl                              129  CH.sub.2 CH.sub.3                                                                          5-pyrimidyl                                                                               5-methyl-1-imidazolyl                              130  CH.sub.2 CH.sub.3                                                                          5-pyrimidyl                                                                               2-methylsulfonyl-1-imidazolyl                      131  CH.sub.2 CH.sub.3                                                                          2-Cl-phenyl                                                                               2-(aminosulfonyl)phenyl                            132  CH.sub.2 CH.sub.3                                                                          2-Cl-phenyl                                                                               2-(methylaminosulfonyl)-                                                       phenyl                                             133  CH.sub.2 CH.sub.3                                                                          2-Cl-phenyl                                                                               1-pyrrolidinocarbonyl                              134  CH.sub.2 CH.sub.3                                                                          2-Cl-phenyl                                                                               2-(methylsulfonyl)phenyl                           135  CH.sub.2 CH.sub.3                                                                          2-Cl-phenyl                                                                               4-morpholino                                       136  CH.sub.2 CH.sub.3                                                                          2-Cl-phenyl                                                                               2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               137  CH.sub.2 CH.sub.3                                                                          2-Cl-phenyl                                                                               4-morpholinocarbonyl                               138  CH.sub.2 CH.sub.3                                                                          2-Cl-phenyl                                                                               2-methyl-1-imidazolyl                              139  CH.sub.2 CH.sub.3                                                                          2-Cl-phenyl                                                                               5-methyl-1-imidazolyl                              140  CH.sub.2 CH.sub.3                                                                          2-Cl-phenyl                                                                               2-methylsulfonyl-1-imidazolyl                      141  CH.sub.2 CH.sub.3                                                                          2-F-phenyl 2-(aminosulfonyl)phenyl                            142  CH.sub.2 CH.sub.3                                                                          2-F-phenyl 2-(methylaminosulfonyl)-                                                       phenyl                                             143  CH.sub.2 CH.sub.3                                                                          2-F-phenyl 1-pyrrolidinocarbonyl                              144  CH.sub.2 CH.sub.3                                                                          2-F-phenyl 2-(methylsulfonyl)phenyl                           145  CH.sub.2 CH.sub.3                                                                          2-F-phenyl 4-morpholino                                       146  CH.sub.2 CH.sub.3                                                                          2-F-phenyl 2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               147  CH.sub.2 CH.sub.3                                                                          2-F-phenyl 4-morpholinocarbonyl                               148  CH.sub.2 CH.sub.3                                                                          2-F-phenyl 2-methyl-1-imidazolyl                              149  CH.sub.2 CH.sub.3                                                                          2-F-phenyl 5-methyl-1-imidazolyl                              150  CH.sub.2 CH.sub.3                                                                          2-F-phenyl 2-methylsulfonyl-1-imidazolyl                      151  CH.sub.2 CH.sub.3                                                                          2,6-diF-phenyl                                                                            2-(aminosulfonyl)phenyl                            152  CH.sub.2 CH.sub.3                                                                          2,6-diF-phenyl                                                                            2-(methylaminosulfonyl)-                                                       phenyl                                             153  CH.sub.2 CH.sub.3                                                                          2,6-diF-phenyl                                                                            1-pyrrolidinocarbonyl                              154  CH.sub.2 CH.sub.3                                                                          2,6-diF-phenyl                                                                            2-(methylsulfonyl)phenyl                           155  CH.sub.2 CH.sub.3                                                                          2,6-diF-phenyl                                                                            4-morpholino                                       156  CH.sub.2 CH.sub.3                                                                          2,6-diF-phenyl                                                                            2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               157  CH.sub.2 CH.sub.3                                                                          2,6-diF-phenyl                                                                            4-morpholinocarbonyl                               158  CH.sub.2 CH.sub.3                                                                          2,6-diF-phenyl                                                                            2-methyl-1-imidazolyl                              159  CH.sub.2 CH.sub.3                                                                          2,6-diF-phenyl                                                                            5-methyl-1-imidazolyl                              160  CH.sub.2 CH.sub.3                                                                          2,6-diF-phenyl                                                                            2-methylsulfonyl-1-imidazolyl                      161  CF.sub.3    phenyl     2-(aminosulfonyl)phenyl                            162  CF.sub.3    phenyl     2-(methylaminosulfonyl)-                                                       phenyl                                             163  CF.sub.3    phenyl     1-pyrrolidinocarbonyl                              164  CF.sub.3    phenyl     2-(methylsulfonyl)phenyl                           165  CF.sub.3    phenyl     4-morpholino                                       166  CF.sub.3    phenyl     2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               167  CF.sub.3    phenyl     4-morpholinocarbonyl                               168  CF.sub.3    phenyl     2-methyl-1-imidazolyl                              169  CF.sub.3    phenyl     5-methyl-1-imidazolyl                              170  CF.sub.3    phenyl     2-methylsulfonyl-1-imidazolyl                      171  CF.sub.3    2-pyridyl  2-(aminosulfonyl)phenyl                            172  CF.sub.3    2-pyridyl  2-(methylaminosulfonyl)-                                                       phenyl                                             173  CF.sub.3    2-pyridyl  1-pyrrolidinocarbonyl                              174  CF.sub.3    2-pyridyl  2-(methylsulfonyl)phenyl                           175  CF.sub.3    2-pyridyl  4-morpholino                                       176  CF.sub.3    2-pyridyl  2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               177  CF.sub.3    2-pyridyl  4-morpholinocarbonyl                               178  CF.sub.3    2-pyridyl  2-methyl-1-imidazolyl                              179  CF.sub.3    2-pyridyl  5-methyl-1-imidazolyl                              180  CF.sub.3    2-pyridyl  2-methylsulfonyl-1-imidazolyl                      181  CF.sub.3    3-pyridyl  2-(aminosulfonyl)phenyl                            182  CF.sub.3    3-pyridyl  2-(methylaminosulfonyl)-                                                       phenyl                                             183  CF.sub.3    3-pyridyl  1-pyrrolidinocarbonyl                              184  CF.sub.3    3-pyridyl  2-(methylsulfonyl)phenyl                           185  CF.sub.3    3-pyridyl  4-morpholino                                       186  CF.sub.3    3-pyridyl  2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               187  CF.sub.3    3-pyridyl  4-morpholinocarbonyl                               188  CF.sub.3    3-pyridyl  2-methyl-1-imidazolyl                              189  CF.sub.3    3-pyridyl  5-methyl-1-imidazolyl                              190  CF.sub.3    3-pyridyl  2-methylsulfonyl-1-imidazolyl                      191  CF.sub.3    2-pyrimidyl                                                                               2-(aminosulfonyl)phenyl                            192  CF.sub.3    2-pyrimidyl                                                                               2-(methylaminosulfonyl)-                                                       phenyl                                             193  CF.sub.3    2-pyrimidyl                                                                               1-pyrrolidinocarbonyl                              194  CF.sub.3    2-pyrimidyl                                                                               2-(methylsulfonyl)phenyl                           195  CF.sub.3    2-pyrimidyl                                                                               4-morpholino                                       196  CF.sub.3    2-pyrimidyl                                                                               2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               197  CF.sub.3    2-pyrimidyl                                                                               4-morpholinocarbonyl                               198  CF.sub.3    2-pyrimidyl                                                                               2-methyl-1-imidazolyl                              199  CF.sub.3    2-pyrimidyl                                                                               5-methyl-1-imidazolyl                              200  CF.sub.3    2-pyrimidyl                                                                               2-methylsulfonyl-1-imidazolyl                      201  CF.sub.3    5-pyrimidyl                                                                               2-(aminosulfonyl)phenyl                            202  CF.sub.3    5-pyrimidyl                                                                               2-(methylaminosulfonyl)-                                                       phenyl                                             203  CF.sub.3    5-pyrimidyl                                                                               1-pyrrolidinocarbonyl                              204  CF.sub.3    5-pyrimidyl                                                                               2-(methylsulfonyl)phenyl                           205  CF.sub.3    5-pyrimidyl                                                                               4-morpholino                                       206  CF.sub.3    5-pyrimidyl                                                                               2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               207  CF.sub.3    5-pyrimidyl                                                                               4-morpholinocarbonyl                               208  CF.sub.3    5-pyrimidyl                                                                               2-methyl-1-imidazolyl                              209  CF.sub.3    5-pyrimidyl                                                                               5-methyl-1-imidazolyl                              210  CF.sub.3    5-pyrimidyl                                                                               2-methylsulfonyl-1-imidazolyl                      211  CF.sub.3    2-Cl-phenyl                                                                               2-(aminosulfonyl)phenyl                            212  CF.sub.3    2-Cl-phenyl                                                                               2-(methylaminosulfonyl)-                                                       phenyl                                             213  CF.sub.3    2-Cl-phenyl                                                                               1-pyrrolidinocarbonyl                              214  CF.sub.3    2-Cl-phenyl                                                                               2-(methylsulfonyl)phenyl                           215  CF.sub.3    2-Cl-phenyl                                                                               4-morpholino                                       216  CF.sub.3    2-Cl-phenyl                                                                               2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               217  CF.sub.3    2-Cl-phenyl                                                                               4-morpholinocarbonyl                               218  CF.sub.3    2-Cl-phenyl                                                                               2-methyl-1-imidazolyl                              219  CF.sub.3    2-Cl-phenyl                                                                               5-methyl-1-imidazolyl                              220  CF.sub.3    2-Cl-phenyl                                                                               2-methylsulfonyl-1-imidazolyl                      221  CF.sub.3    2-F-phenyl 2-(aminosulfonyl)phenyl                            222  CF.sub.3    2-F-phenyl 2-(methylaminosulfonyl)-                                                       phenyl                                             223  CF.sub.3    2-F-phenyl 1-pyrrolidinocarbonyl                              224  CF.sub.3    2-F-phenyl 2-(methylsulfonyl)phenyl                           225  CF.sub.3    2-F-phenyl 4-morpholino                                       226  CF.sub.3    2-F-phenyl 2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               227  CF.sub.3    2-F-phenyl 4-morpholinocarbonyl                               228  CF.sub.3    2-F-phenyl 2-methyl-1-imidazolyl                              229  CF.sub.3    2-F-phenyl 5-methyl-1-imidazolyl                              230  CF.sub.3    2-F-phenyl 2-methylsulfonyl-1-imidazolyl                      231  CF.sub.3    2,6-diF-phenyl                                                                            2-(aminosulfonyl)phenyl                            232  CF.sub.3    2,6-diF-phenyl                                                                            2-(methylaminosulfonyl)-                                                       phenyl                                             233  CF.sub.3    2,6-diF-phenyl                                                                            1-pyrrolidinocarbonyl                              234  CF.sub.3    2,6-diF-phenyl                                                                            2-(methylsulfonyl)phenyl                           235  CF.sub.3    2,6-diF-phenyl                                                                            4-morpholino                                       236  CF.sub.3    2,6-diF-phenyl                                                                            2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               237  CF.sub.3    2,6-diF-phenyl                                                                            4-morpholinocarbonyl                               238  CF.sub.3    2,6-diF-phenyl                                                                            2-methyl-1-imidazolyl                              239  CF.sub.3    2,6-diF-phenyl                                                                            5-methyl-1-imidazolyl                              240  CF.sub.3    2,6-diF-phenyl                                                                            2-methylsulfonyl-1-imidazolyl                      241  SCH.sub.3   phenyl     2-(aminosulfonyl)phenyl                            242  SCH.sub.3   phenyl     2-(methylaminosulfonyl)-                                                       phenyl                                             243  SCH.sub.3   phenyl     1-pyrrolidinocarbonyl                              244  SCH.sub.3   phenyl     2-(methylsulfonyl)phenyl                           245  SCH.sub.3   phenyl     4-morpholino                                       246  SCH.sub.3   phenyl     2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               247  SCH.sub.3   phenyl     4-morpholinocarbonyl                               248  SCH.sub.3   phenyl     2-methyl-1-imidazolyl                              249  SCH.sub.3   phenyl     5-methyl-1-imidazolyl                              250  SCH.sub.3   phenyl     2-methylsulfonyl-1-imidazolyl                      251  SCH.sub.3   2-pyridyl  2-(aminosulfonyl)phenyl                            252  SCH.sub.3   2-pyridyl  2-(methylaminosulfonyl)-                                                       phenyl                                             253  SCH.sub.3   2-pyridyl  1-pyrrolidinocarbonyl                              254  SCH.sub.3   2-pyridyl  2-(methylsulfonyl)phenyl                           255  SCH.sub.3   2-pyridyl  4-morpholino                                       256  SCH.sub.3   2-pyridyl  2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               257  SCH.sub.3   2-pyridyl  4-morpholinocarbonyl                               258  SCH.sub.3   2-pyridyl  2-methyl-1-imidazolyl                              259  SCH.sub.3   2-pyridyl  5-methyl-1-imidazolyl                              260  SCH.sub.3   2-pyridyl  2-methylsulfonyl-1-imidazolyl                      261  SCH.sub.3   3-pyridyl  2-(aminosulfonyl)phenyl                            262  SCH.sub.3   3-pyridyl  2-(methylaminosulfonyl)-                                                       phenyl                                             263  SCH.sub.3   3-pyridyl  1-pyrrolidinocarbonyl                              264  SCH.sub.3   3-pyridyl  2-(methylsulfonyl)phenyl                           265  SCH.sub.3   3-pyridyl  4-morpholino                                       266  SCH.sub.3   3-pyridyl  2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               267  SCH.sub.3   5-pyridyl  4-morpholinocarbonyl                               268  SCH.sub.3   5-pyridyl  2-methyl-1-imidazolyl                              269  SCH.sub.3   5-pyridyl  5-methyl-1-imidazolyl                              270  SCH.sub.3   5-pyridyl  2-methylsulfonyl-1-imidazolyl                      271  SCH.sub.3   2-pyrimidyl                                                                               2-(aminosulfonyl)phenyl                            272  SCH.sub.3   2-pyrimidyl                                                                               2-(methylaminosulfonyl)-                                                       phenyl                                             273  SCH.sub.3   2-pyrimidyl                                                                               1-pyrrolidinocarbonyl                              274  SCH.sub.3   2-pyrimidyl                                                                               2-(methylsulfonyl)phenyl                           275  SCH.sub.3   2-pyrimidyl                                                                               4-morpholino                                       276  SCH.sub.3   2-pyrimidyl                                                                               2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               277  SCH.sub.3   2-pyrimidyl                                                                               4-morpholinocarbonyl                               278  SCH.sub.3   2-pyrimidyl                                                                               2-methyl-1-imidazolyl                              279  SCH.sub.3   2-pyrimidyl                                                                               5-methyl-1-imidazolyl                              280  SCH.sub.3   2-pyrimidyl                                                                               2-methylsulfonyl-1-imidazolyl                      281  SCH.sub.3   5-pyrimidyl                                                                               2-(aminosulfonyl)phenyl                            282  SCH.sub.3   5-pyrimidyl                                                                               2-(methylaminosulfonyl)-                                                       phenyl                                             283  SCH.sub.3   5-pyrimidyl                                                                               1-pyrrolidinocarbonyl                              284  SCH.sub.3   5-pyrimidyl                                                                               2-(methylsulfonyl)phenyl                           285  SCH.sub.3   5-pyrimidyl                                                                               4-morpholino                                       286  SCH.sub.3   5-pyrimidyl                                                                               2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               287  SCH.sub.3   5-pyrimidyl                                                                               4-morpholinocarbonyl                               288  SCH.sub.3   5-pyrimidyl                                                                               2-methyl-1-imidazolyl                              289  SCH.sub.3   5-pyrimidyl                                                                               5-methyl-1-imidazolyl                              290  SCH.sub.3   5-pyrimidyl                                                                               2-methylsulfonyl-1-imidazolyl                      291  SCH.sub.3   2-Cl-phenyl                                                                               2-(aminosulfonyl)phenyl                            292  SCH.sub.3   2-Cl-phenyl                                                                               2-(methylaminosulfonyl)-                                                       phenyl                                             293  SCH.sub.3   2-Cl-phenyl                                                                               1-pyrrolidinocarbonyl                              294  SCH.sub.3   2-Cl-phenyl                                                                               2-(methylsulfonyl)phenyl                           295  SCH.sub.3   2-Cl-phenyl                                                                               4-morpholino                                       296  SCH.sub.3   2-Cl-phenyl                                                                               2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               297  SCH.sub.3   2-Cl-phenyl                                                                               4-morpholinocarbonyl                               298  SCH.sub.3   2-Cl-phenyl                                                                               2-methyl-1-imidazolyl                              299  SCH.sub.3   2-Cl-phenyl                                                                               5-methyl-1-imidazolyl                              300  SCH.sub.3   2-Cl-phenyl                                                                               2-methylsulfonyl-1-imidazolyl                      301  SCH.sub.3   2-F-phenyl 2-(aminosulfonyl)phenyl                            302  SCH.sub.3   2-F-phenyl 2-(methylaminosulfonyl)-                                                       phenyl                                             303  SCH.sub.3   2-F-phenyl 1-pyrrolidinocarbonyl                              304  SCH.sub.3   2-F-phenyl 2-(methylsulfonyl)phenyl                           305  SCH.sub.3   2-F-phenyl 4-morpholino                                       306  SCH.sub.3   2-F-phenyl 2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               307  SCH.sub.3   2-F-phenyl 4-morpholinocarbonyl                               308  SCH.sub.3   2-F-phenyl 2-methyl-1-imidazolyl                              309  SCH.sub.3   2-F-phenyl 5-methyl-1-imidazolyl                              310  SCH.sub.3   2-F-phenyl 2-methylsulfonyl-1-imidazolyl                      311  SCH.sub.3   2,6-diF-phenyl                                                                            2-(aminosulfonyl)phenyl                            312  SCH.sub.3   2,6-diF-phenyl                                                                            2-(methylaminosulfonyl)-                                                       phenyl                                             313  SCH.sub.3   2,6-diF-phenyl                                                                            1-pyrrolidinocarbonyl                              314  SCH.sub.3   2,6-diF-phenyl                                                                            2-(methylsulfonyl)phenyl                           315  SCH.sub.3   2,6-diF-phenyl                                                                            4-morpholino                                       316  SCH.sub.3   2,6-diF-phenyl                                                                            2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               317  SCH.sub.3   2,6-diF-phenyl                                                                            4-morpholinocarbonyl                               318  SCH.sub.3   2,6-diF-phenyl                                                                            2-methyl-1-imidazolyl                              319  SCH.sub.3   2,6-diF-phenyl                                                                            5-methyl-1-imidazolyl                              320  SCH.sub.3   2,6-diF-phenyl                                                                            2-methylsulfonyl-1-imidazolyl                      321  SOCH.sub.3  phenyl     2-(aminosulfonyl)phenyl                            322  SOCH.sub.3  phenyl     2-(methylaminosulfonyl)-                                                       phenyl                                             323  SOCH.sub.3  phenyl     1-pyrrolidinocarbonyl                              324  SOCH.sub.3  phenyl     2-(methylsulfonyl)phenyl                           325  SOCH.sub.3  phenyl     4-morpholino                                       326  SOCH.sub.3  phenyl     2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               327  SOCH.sub.3  phenyl     4-morpholinocarbonyl                               328  SOCH.sub.3  phenyl     2-methyl-1-imidazolyl                              329  SOCH.sub.3  phenyl     5-methyl-1-imidazolyl                              330  SOCH.sub.3  phenyl     2-methylsulfonyl-1-imidazolyl                      331  SOCH.sub.3  2-pyridyl  2-(aminosulfonyl)phenyl                            332  SOCH.sub.3  2-pyridyl  2-(methylaminosulfonyl)-                                                       phenyl                                             333  SOCH.sub.3  2-pyridyl  1-pyrrolidinocarbonyl                              334  SOCH.sub.3  2-pyridyl  2-(methylsulfonyl)phenyl                           335  SOCH.sub.3  2-pyridyl  4-morpholino                                       336  SOCH.sub.3  2-pyridyl  2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               337  SOCH.sub.3  2-pyridyl  4-morpholinocarbonyl                               338  SOCH.sub.3  2-pyridyl  2-methyl-1-imidazolyl                              339  SOCH.sub.3  2-pyridyl  5-methyl-1-imidazolyl                              340  SOCH.sub.3  2-pyridyl  2-methylsulfonyl-1-imidazolyl                      341  SOCH.sub.3  3-pyridyl  2-(aminosulfonyl)phenyl                            342  SOCH.sub.3  3-pyridyl  2-(methylaminosulfonyl)-                                                       phenyl                                             343  SOCH.sub.3  3-pyridyl  1-pyrrolidinocarbonyl                              344  SOCH.sub.3  3-pyridyl  2-(methylsulfonyl)phenyl                           345  SOCH.sub.3  3-pyridyl  4-morpholino                                       346  SOCH.sub.3  3-pyridyl  2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               347  SOCH.sub.3  3-pyridyl  4-morpholinocarbonyl                               348  SOCH.sub.3  3-pyridyl  2-methyl-1-imidazolyl                              349  SOCH.sub.3  3-pyridyl  5-methyl-1-imidazolyl                              350  SOCH.sub.3  3-pyridyl  2-methylsulfonyl-1-imidazolyl                      351  SOCH.sub.3  2-pyrimidyl                                                                               2-(aminosulfonyl)phenyl                            352  SOCH.sub.3  2-pyrimidyl                                                                               2-(methylaminosulfonyl)                                                        phenyl                                             353  SOCH.sub.3  2-pyrimidyl                                                                               1-pyrrolidinocarbonyl                              354  SOCH.sub.3  2-pyrimidyl                                                                               2-(methylsulfonyl)phenyl                           355  SOCH.sub.3  2-pyrimidyl                                                                               4-morpholino                                       356  SOCH.sub.3  2-pyrimidyl                                                                               2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               357  SOCH.sub.3  2-pyrimidyl                                                                               4-morpholinocarbonyl                               358  SOCH.sub.3  2-pyrimidyl                                                                               2-methyl-1-imidazolyl                              359  SOCH.sub.3  2-pyrimidyl                                                                               5-methyl-1-imidazolyl                              360  SOCH.sub.3  2-pyrimidyl                                                                               2-methylsulfonyl-1-imidazolyl                      361  SOCH.sub.3  5-pyrimidyl                                                                               2-(aminosulfonyl)phenyl                            362  SOCH.sub.3  5-pyrimidyl                                                                               2-(methylaminosulfonyl)-                                                       phenyl                                             363  SOCH.sub.3  5-pyrimidyl                                                                               1-pyrrolidinocarbonyl                              364  SOCH.sub.3  5-pyrimidyl                                                                               2-(methylsulfonyl)phenyl                           365  SOCH.sub.3  5-pyrimidyl                                                                               4-morpholino                                       366  SOCH.sub.3  5-pyrimidyl                                                                               2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               367  SOCH.sub.3  5-pyrimidyl                                                                               4-morpholinocarbonyl                               368  SOCH.sub.3  5-pyrimidyl                                                                               2-methyl-1-imidazolyl                              369  SOCH.sub.3  5-pyrimidyl                                                                               5-methyl-1-imidazolyl                              370  SOCH.sub.3  5-pyrimidyl                                                                               2-methylsulfonyl-1-imidazolyl                      371  SOCH.sub.3  2-Cl-phenyl                                                                               2-(aminosulfonyl)phenyl                            372  SOCH.sub.3  2-Cl-phenyl                                                                               2-(methylaminosulfonyl)-                                                       phenyl                                             373  SOCH.sub.3  2-Cl-phenyl                                                                               1-pyrrolidinocarbonyl                              374  SOCH.sub.3  2-Cl-phenyl                                                                               2-(methylsulfonyl)phenyl                           375  SOCH.sub.3  2-Cl-phenyl                                                                               4-morpholino                                       376  SOCH.sub.3  2-Cl-phenyl                                                                               2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               377  SOCH.sub.3  2-Cl-phenyl                                                                               4-morpholinocarbonyl                               378  SOCH.sub.3  2-Cl-phenyl                                                                               2-methyl-1-imidazolyl                              379  SOCH.sub.3  2-Cl-phenyl                                                                               5-methyl-1-imidazolyl                              380  SOCH.sub.3  2-Cl-phenyl                                                                               2-methylsulfonyl-1-imidazolyl                      381  SOCH.sub.3  2-F-phenyl 2-(aminosulfonyl)phenyl                            382  SOCH.sub.3  2-F-phenyl 2-(methylaminosulfonyl)-                                                       phenyl                                             383  SOCH.sub.3  2-F-phenyl 1-pyrrolidinocarbonyl                              384  SOCH.sub.3  2-F-phenyl 2-(methylsulfonyl)phenyl                           385  SOCH.sub.3  2-F-phenyl 4-morpholino                                       386  SOCH.sub.3  2-F-phenyl 2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               387  SOCH.sub.3  2-F-phenyl 4-morpholinocarbonyl                               388  SOCH.sub.3  2-F-phenyl 2-methyl-1-imidazolyl                              389  SOCH.sub.3  2-F-phenyl 5-methyl-1-imidazolyl                              390  SOCH.sub.3  2-F-phenyl 2-methylsulfonyl-1-imidazolyl                      391  SOCH.sub.3  2,6-diF-phenyl                                                                            2-(aminosulfonyl)phenyl                            392  SOCH.sub.3  2,6-diF-phenyl                                                                            2-(methylaminosulfonyl)-                                                       phenyl                                             393  SOCH.sub.3  2,6-diF-phenyl                                                                            1-pyrrolidinocarbonyl                              394  SOCH.sub.3  2,6-diF-phenyl                                                                            2-(methylsulfonyl)phenyl                           395  SOCH.sub.3  2,6-diF-phenyl                                                                            4-morpholino                                       396  SOCH.sub.3  2,6-diF-phenyl                                                                            2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               397  SOCH.sub.3  2,6-diF-phenyl                                                                            4-morpholinocarbonyl                               398  SOCH.sub.3  2,6-diF-phenyl                                                                            2-methyl-1-imidazolyl                              399  SOCH.sub.3  2,6-diF-phenyl                                                                            5-methyl-1-imidazolyl                              400  SOCH.sub.3  2,6-diF-phenyl                                                                            2-methylsulfonyl-1-imidazolyl                      401  SO.sub.2 CH.sub.3                                                                          phenyl     2-(aminosulfonyl)phenyl                            402  SO.sub.2 CH.sub.3                                                                          phenyl     2-(methylaminosulfonyl)-                                                       phenyl                                             403  SO.sub.2 CH.sub.3                                                                          phenyl     1-pyrrolidinocarbonyl                              404  SO.sub.2 CH.sub.3                                                                          phenyl     2-(methylsulfonyl)phenyl                           405  SO.sub.2 CH.sub.3                                                                          phenyl     4-morpholino                                       406  SO.sub.2 CH.sub.3                                                                          phenyl     2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               407  SO.sub.2 CH.sub.3                                                                          phenyl     4-morpholinocarbonyl                               408  SO.sub.2 CH.sub.3                                                                          phenyl     2-methyl-1-imidazolyl                              409  SO.sub.2 CH.sub.3                                                                          phenyl     5-methyl-1-imidazolyl                              410  SO.sub.2 CH.sub.3                                                                          phenyl     2-methylsulfonyl-1-imidazolyl                      411  SO.sub.2 CH.sub.3                                                                          2-pyridyl  2-(aminosulfonyl)phenyl                            412  SO.sub.2 CH.sub.3                                                                          2-pyridyl  2-(methylaminosulfonyl)-                                                       phenyl                                             413  SO.sub.2 CH.sub.3                                                                          2-pyridyl  1-pyrrolidinocarbonyl                              414  SO.sub.2 CH.sub.3                                                                          2-pyridyl  2-(methylsulfonyl)phenyl                           415  SO.sub.2 CH.sub.3                                                                          2-pyridyl  4-morpholino                                       416  SO.sub.2 CH.sub.3                                                                          2-pyridyl  2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               417  SO.sub.2 CH.sub.3                                                                          2-pyridyl  4-morpholinocarbonyl                               418  SO.sub.2 CH.sub.3                                                                          2-pyridyl  2-methyl-1-imidazolyl                              419  SO.sub.2 CH.sub.3                                                                          2-pyridyl  5-methyl-1-imidazolyl                              420  SO.sub.2 CH.sub.3                                                                          2-pyridyl  2-methylsulfonyl-1-imidazolyl                      421  SO.sub.2 CH.sub.3                                                                          3-pyridyl  2-(aminosulfonyl)phenyl                            422  SO.sub.2 CH.sub.3                                                                          3-pyridyl  2-(methylaminosulfonyl)-                                                       phenyl                                             423  SO.sub.2 CH.sub.3                                                                          3-pyridyl  1-pyrrolidinocarbonyl                              424  SO.sub.2 CH.sub.3                                                                          3-pyridyl  2-(methylsulfonyl)phenyl                           425  SO.sub.2 CH.sub.3                                                                          3-pyridyl  4-morpholino                                       426  SO.sub.2 CH.sub.3                                                                          3-pyridyl  2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               427  SO.sub.2 CH.sub.3                                                                          3-pyridyl  4-morpholinocarbonyl                               428  SO.sub.2 CH.sub.3                                                                          3-pyridyl  2-methyl-1-imidazolyl                              429  SO.sub.2 CH.sub.3                                                                          3-pyridyl  5-methyl-1-imidazolyl                              430  SO.sub.2 CH.sub.3                                                                          3-pyridyl  2-methylsulfonyl-1-imidazolyl                      431  SO.sub.2 CH.sub.3                                                                          2-pyrimidyl                                                                               2-(aminosulfonyl)phenyl                            432  SO.sub.2 CH.sub.3                                                                          2-pyrimidyl                                                                               2-(methylaminosulfonyl)-                                                       phenyl                                             433  SO.sub.2 CH.sub.3                                                                          2-pyrimidyl                                                                               1-pyrrolidinocarbonyl                              434  SO.sub.2 CH.sub.3                                                                          2-pyrimidyl                                                                               2-(methylsulfonyl)phenyl                           435  SO.sub.2 CH.sub.3                                                                          2-pyrimidyl                                                                               4-morpholino                                       436  SO.sub.2 CH.sub.3                                                                          2-pyrimidyl                                                                               2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               437  SO.sub.2 CH.sub.3                                                                          2-pyrimidyl                                                                               4-morpholinocarbonyl                               438  SO.sub.2 CH.sub.3                                                                          2-pyrimidyl                                                                               2-methyl-1-imidazolyl                              439  SO.sub.2 CH.sub.3                                                                          2-pyrimidyl                                                                               5-methyl-1-imidazolyl                              440  SO.sub.2 CH.sub.3                                                                          2-pyrimidyl                                                                               2-methylsulfonyl-1-imidazolyl                      441  SO.sub.2 CH.sub.3                                                                          5-pyrimidyl                                                                               2-(aminosulfonyl)phenyl                            442  SO.sub.2 CH.sub.3                                                                          5-pyrimidyl                                                                               2-(methylaminosulfonyl)-                                                       phenyl                                             443  SO.sub.2 CH.sub.3                                                                          5-pyrimidyl                                                                               1-pyrrolidinocarbonyl                              444  SO.sub.2 CH.sub.3                                                                          5-pyrimidyl                                                                               2-(methylsulfonyl)phenyl                           445  SO.sub.2 CH.sub.3                                                                          5-pyrimidyl                                                                               4-morpholino                                       446  SO.sub.2 CH.sub.3                                                                          5-pyrimidyl                                                                               2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               447  SO.sub.2 CH.sub.3                                                                          5-pyrimidyl                                                                               4-morpholinocarbonyl                               448  SO.sub.2 CH.sub.3                                                                          5-pyrimidyl                                                                               2-methyl-1-imidazolyl                              449  SO.sub.2 CH.sub.3                                                                          5-pyrimidyl                                                                               5-methyl-1-imidazolyl                              450  SO.sub.2 CH.sub.3                                                                          5-pyrimidyl                                                                               2-methylsulfonyl-1-imidazolyl                      451  SO.sub.2 CH.sub.3                                                                          2-Cl-phenyl                                                                               2-(aminosulfonyl)phenyl                            452  SO.sub.2 CH.sub.3                                                                          2-Cl-phenyl                                                                               2-(methylaminosulfonyl)-                                                       phenyl                                             453  SO.sub.2 CH.sub.3                                                                          2-Cl-phenyl                                                                               1-pyrrolidinocarbonyl                              454  SO.sub.2 CH.sub.3                                                                          2-Cl-phenyl                                                                               2-(methylsulfonyl)phenyl                           455  SO.sub.2 CH.sub.3                                                                          2-Cl-phenyl                                                                               4-morpholino                                       456  SO.sub.2 CH.sub.3                                                                          2-Cl-phenyl                                                                               2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               457  SO.sub.2 CH.sub.3                                                                          2-Cl-phenyl                                                                               4-morpholinocarbonyl                               458  SO.sub.2 CH.sub.3                                                                          2-Cl-phenyl                                                                               2-methyl-1-imidazolyl                              459  SO.sub.2 CH.sub.3                                                                          2-Cl-phenyl                                                                               5-methyl-1-imidazolyl                              460  SO.sub.2 CH.sub.3                                                                          2-Cl-phenyl                                                                               2-methylsulfonyl-1-imidazolyl                      461  SO.sub.2 CH.sub.3                                                                          2-F-phenyl 2-(aminosulfonyl)phenyl                            462  SO.sub.2 CH.sub.3                                                                          2-F-phenyl 2-(methylaminosulfonyl)-                                                       phenyl                                             463  SO.sub.2 CH.sub.3                                                                          2-F-phenyl 1-pyrrolidinocarbonyl                              464  SO.sub.2 CH.sub.3                                                                          2-F-phenyl 2-(methylsulfonyl)phenyl                           465  SO.sub.2 CH.sub.3                                                                          2-F-phenyl 4-morpholino                                       466  SO.sub.2 CH.sub.3                                                                          2-F-phenyl 2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               467  SO.sub.2 CH.sub.3                                                                          2-F-phenyl 4-morpholinocarbonyl                               468  SO.sub.2 CH.sub.3                                                                          2-F-phenyl 2-methyl-1-imidazolyl                              469  SO.sub.2 CH.sub.3                                                                          2-F-phenyl 5-methyl-1-imidazolyl                              470  SO.sub.2 CH.sub.3                                                                          2-F-phenyl 2-methylsulfonyl-1-imidazolyl                      471  SO.sub.2 CH.sub.3                                                                          2,6-diF-phenyl                                                                            2-(aminosulfonyl)phenyl                            472  SO.sub.2 CH.sub.3                                                                          2,6-diF-phenyl                                                                            2-(methylaminosulfonyl)-                                                       phenyl                                             473  SO.sub.2 CH.sub.3                                                                          2,6-diF-phenyl                                                                            1-pyrrolidinocarbonyl                              474  SO.sub.2 CH.sub.3                                                                          2,6-diF-phenyl                                                                            2-(methylsulfonyl)phenyl                           475  SO.sub.2 CH.sub.3                                                                          2,6-diF-phenyl                                                                            4-morpholino                                       476  SO.sub.2 CH.sub.3                                                                          2,6-diF-phenyl                                                                            2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               477  SO.sub.2 CH.sub.3                                                                          2,6-diF-phenyl                                                                            4-morpholinocarbonyl                               478  SO.sub.2 CH.sub.3                                                                          2,6-diF-phenyl                                                                            2-methyl-1-imidazolyl                              479  SO.sub.2 CH.sub.3                                                                          2,6-diF-phenyl                                                                            5-methyl-1-imidazolyl                              480  SO.sub.2 CH.sub.3                                                                          2,6-diF-phenyl                                                                            2-methylsulfonyl-1-imidazolyl                      481  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             phenyl     2-(aminosulfonyl)phenyl                            482  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             phenyl     2-(methylaminosulfonyl)-                                                       phenyl                                             483  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             phenyl     1-pyrrolidinocarbonyl                              484  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             phenyl     2-(methylsulfonyl)phenyl                           485  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             phenyl     4-morpholino                                       486  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             phenyl     2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               487  CH2NH--SO.sub.2 CH.sub.3                                                                   phenyl     4-morpholinocarbonyl                               488  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             phenyl     2-methyl-1-imidazolyl                              489  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             phenyl     5-methyl-1-imidazolyl                              490  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             phenyl     2-methylsulfonyl-1-imidazolyl                      491  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2-pyridyl  2-(aminosulfonyl)phenyl                            492  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2-pyridyl  2-(methylaminosulfonyl)-                                                       phenyl                                             493  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2-pyridyl  1-pyrrolidinocarbonyl                              494  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2-pyridyl  2-(methylsulfonyl)phenyl                           495  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2-pyridyl  4-morpholino                                       496  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2-pyridyl  2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               497  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2-pyridyl  4-morpholinocarbonyl                               498  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2-pyridyl  2-methyl-1-imidazolyl                              499  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2-pyridyl  5-methyl-1-imidazolyl                              500  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2-pyridyl  2-methylsulfonyl-1-imidazolyl                      501  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             3-pyridyl  2-(aminosulfonyl)phenyl                            502  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             3-pyridyl  2-(methylaminosulfonyl)-                                                       phenyl                                             503  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             3-pyridyl  1-pyrrolidinocarbonyl                              504  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             3-pyridyl  2-(methylsulfonyl)phenyl                           505  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             3-pyridyl  4-morpholino                                       506  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             3-pyridyl  2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               507  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             3-pyridyl  4-morpholinocarbonyl                               508  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             3-pyridyl  2-methyl-1-imidazolyl                              509  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             3-pyridyl  5-methyl-1-imidazolyl                              510  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             3-pyridyl  2-methylsulfonyl-1-imidazolyl                      511  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2-pyrimidyl                                                                               2-(aminosulfonyl)phenyl                            512  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2-pyrimidyl                                                                               2-(methylaminosulfonyl)-                                                       phenyl                                             513  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2-pyrimidyl                                                                               1-pyrrolidinocarbonyl                              514  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2-pyrimidyl                                                                               2-(methylsulfonyl)phenyl                           515  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2-pyrimidyl                                                                               4-morpholino                                       516  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2-pyrimidyl                                                                               2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               517  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2-pyrimidyl                                                                               4-morpholinocarbonyl                               518  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2-pyrimidyl                                                                               2-methyl-1-imidazolyl                              519  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2-pyrimidyl                                                                               5-methyl-1-imidazolyl                              520  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2-pyrimidyl                                                                               2-methylsulfonyl-1-imidazolyl                      521  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             5-pyrimidyl                                                                               2-(aminosulfonyl)phenyl                            522  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             5-pyrimidyl                                                                               2-(methylaminosulfonyl)-                                                       phenyl                                             523  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             5-pyrimidyl                                                                               1-pyrrolidinocarbonyl                              524  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             5-pyrimidyl                                                                               2-(methylsulfonyl)phenyl                           525  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             5-pyrimidyl                                                                               4-morpholino                                       526  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             5-pyrimidyl                                                                               2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               527  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             5-pyrimidyl                                                                               4-morpholinocarbonyl                               528  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             5-pyrimidyl                                                                               2-methyl-1-imidazolyl                              529  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             5-pyrimidyl                                                                               5-methyl-1-imidazolyl                              530  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             5-pyrimidyl                                                                               2-methylsulfonyl-1-imidazolyl                      531  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2-Cl-phenyl                                                                               2-(aminosulfonyl)phenyl                            532  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2-Cl-phenyl                                                                               2-(methylaminosulfonyl)-                                                       phenyl                                             533  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2-Cl-phenyl                                                                               1-pyrrolidinocarbonyl                              534  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2-Cl-phenyl                                                                               2-(methylsulfonyl)phenyl                           535  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2-Cl-phenyl                                                                               4-morpholino                                       536  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2-Cl-phenyl                                                                               2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               537  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2-Cl-phenyl                                                                               4-morpholinocarbonyl                               538  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2-Cl-phenyl                                                                               2-methyl-1-imidazolyl                              539  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2-Cl-phenyl                                                                               5-methyl-1-imidazolyl                              540  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2-Cl-phenyl                                                                               2-methylsulfonyl-1-imidazolyl                      541  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2-F-phenyl 2-(aminosulfonyl)phenyl                            542  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2-F-phenyl 2-(methylaminosulfonyl)-                                                       phenyl                                             543  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2-F-phenyl 1-pyrrolidinocarbonyl                              544  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2-F-phenyl 2-(methylsulfonyl)phenyl                           545  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2-F-phenyl 4-morpholino                                       546  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2-F-phenyl 2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               547  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2-F-phenyl 4-morpholinocarbonyl                               548  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2-F-phenyl 2-methyl-1-imidazolyl                              549  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2-F-phenyl 5-methyl-1-imidazolyl                              550  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2-F-phenyl                                                    methylsulfonyl-1-imidazolyl                                                    551  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2,6-diF-phenyl                                                                            2-(aminosulfonyl)phenyl                            552  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2,6-diF-phenyl                                                                            2-(methylaminosulfonyl)-                                                       phenyl                                             553  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2,6-diF-phenyl                                                                            1-pyrrolidinocarbonyl                              554  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2,6-diF-phenyl                                                                            2-(methylsulfonyl)phenyl                           555  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2,6-diF-phenyl                                                                            4-morpholino                                       556  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2,6-diF-phenyl                                                                            2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               557  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2,6-diF-phenyl                                                                            4-morpholinocarbonyl                               558  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2,6-diF-phenyl                                                                            2-methyl-1-imidazolyl                              559  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2,6-diF-phenyl                                                                            5-methyl-1-imidazolyl                              560  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2,6-diF-phenyl                                                                            2-methylsulfonyl-1-imidazolyl                      561  Cl          phenyl     2-(aminosulfonyl)phenyl                            562  Cl          phenyl     2-(methylaminosulfonyl)-                                                       phenyl                                             563  Cl          phenyl     1-pyrrolidinocarbonyl                              564  Cl          phenyl     2-(methylsulfonyl)phenyl                           565  Cl          phenyl     4-morpholino                                       566  Cl          phenyl     2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               567  Cl          phenyl     4-morpholinocarbonyl                               568  Cl          phenyl     2-methyl-1-imidazolyl                              569  Cl          phenyl     5-methyl-1-imidazolyl                              570  Cl          phenyl     2-methylsulfonyl-1-imidazolyl                      571  Cl          2-pyridyl  2-(aminosulfonyl)phenyl                            572  Cl          2-pyridyl  2-(methylaminosulfonyl)-                                                       phenyl                                             573  Cl          2-pyridyl  1-pyrrolidinocarbonyl                              574  Cl          2-pyridyl  2-(methylsulfonyl)phenyl                           575  Cl          2-pyridyl  4-morpholino                                       576  Cl          2-pyridyl  2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               577  Cl          2-pyridyl  4-morpholinocarbonyl                               578  Cl          2-pyridyl  2-methyl-1-imidazolyl                              579  Cl          2-pyridyl  5-methyl-1-imidazolyl                              580  Cl          2-pyridyl  2-methylsulfonyl-1-imidazolyl                      581  Cl          3-pyridyl  2-(aminosulfonyl)phenyl                            582  Cl          3-pyridyl  2-(methylaminosulfonyl)-                                                       phenyl                                             583  Cl          3-pyridyl  1-pyrrolidinocarbonyl                              584  Cl          3-pyridyl  2-(methylsulfonyl)phenyl                           585  Cl          3-pyridyl  4-morpholino                                       586  Cl          3-pyridyl  2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               587  Cl          3-pyridyl  4-morpholinocarbonyl                               588  Cl          3-pyridyl  2-methyl-1-imidazolyl                              589  Cl          3-pyridyl  5-methyl-1-imidazolyl                              590  Cl          3-pyridyl  2-methylsulfonyl-1-imidazolyl                      591  Cl          2-pyrimidyl                                                                               2-(aminosulfonyl)phenyl                            592  Cl          2-pyrimidyl                                                                               2-(methylaminosulfonyl)-                                                       phenyl                                             593  Cl          2-pyrimidyl                                                                               1-pyrrolidinocarbonyl                              594  Cl          2-pyrimidyl                                                                               2-(methylsulfonyl)phenyl                           595  Cl          2-pyrimidyl                                                                               4-morpholino                                       596  Cl          2-pyrimidyl                                                                               2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               597  Cl          2-pyrimidyl                                                                               4-morpholinocarbonyl                               598  Cl          2-pyrimidyl                                                                               2-methyl-1-imidazolyl                              599  Cl          2-pyrimidyl                                                                               5-methyl-1-imidazolyl                              600  Cl          2-pyrimidyl                                                                               2-methylsulfonyl-1-imidazolyl                      601  Cl          5-pyrimidyl                                                                               2-(aminosulfonyl)phenyl                            602  Cl          5-pyrimidyl                                                                               2-(methylaminosulfonyl)-                                                       phenyl                                             603  Cl          5-pyrimidyl                                                                               1-pyrrolidinocarbonyl                              604  Cl          5-pyrimidyl                                                                               2-(methylsulfonyl)phenyl                           605  Cl          5-pyrimidyl                                                                               4-morpholino                                       606  Cl          5-pyrimidyl                                                                               2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               607  Cl          5-pyrimidyl                                                                               4-morpholinocarbonyl                               608  Cl          5-pyrimidyl                                                                               2-methyl-1-imidazolyl                              609  Cl          5-pyrimidyl                                                                               5-methyl-1-imidazolyl                              610  Cl          5-pyrimidyl                                                                               2-methylsulfonyl-1-imidazolyl                      611  Cl          2-Cl-phenyl                                                                               2-(aminosulfonyl)phenyl                            612  Cl          2-Cl-phenyl                                                                               2-(methylaminosulfonyl)-                                                       phenyl                                             613  Cl          2-Cl-phenyl                                                                               1-pyrrolidinocarbonyl                              614  Cl          2-Cl-phenyl                                                                               2-(methylsulfonyl)phenyl                           615  Cl          2-Cl-phenyl                                                                               4-morpholino                                       616  Cl          2-Cl-phenyl                                                                               2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               617  Cl          2-Cl-phenyl                                                                               4-morpholinocarbonyl                               618  Cl          2-Cl-phenyl                                                                               2-methyl-1-imidazolyl                              619  Cl          2-Cl-phenyl                                                                               5-methyl-1-imidazolyl                              620  Cl          2-Cl-phenyl                                                                               2-methylsulfonyl-1-imidazolyl                      621  Cl          2-F-phenyl 2-(aminosulfonyl)phenyl                            622  Cl          2-F-phenyl 2-(methylaminosulfonyl)-                                                       phenyl                                             623  Cl          2-F-phenyl 1-pyrrolidinocarbonyl                              624  Cl          2-F-phenyl 2-(methylsulfonyl)phenyl                           625  Cl          2-F-phenyl 4-morpholino                                       626  Cl          2-F-phenyl 2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               627  Cl          2-F-phenyl 4-morpholinocarbonyl                               628  Cl          2-F-phenyl 2-methyl-1-imidazolyl                              629  Cl          2-F-phenyl 5-methyl-1-imidazolyl                              630  Cl          2-F-phenyl 2-methylsulfonyl-1-imidazolyl                      631  Cl          2,6-diF-phenyl                                                                            2-(aminosulfonyl)phenyl                            632  Cl          2,6-diF-phenyl                                                                            2-(methylaminosulfonyl)-                                                       phenyl                                             633  Cl          2,6-diF-phenyl                                                                            1-pyrrolidinocarbonyl                              634  Cl          2,6-diF-phenyl                                                                            2-(methylsulfonyl)phenyl                           635  Cl          2,6-diF-phenyl                                                                            4-morpholino                                       636  Cl          2,6-diF-phenyl                                                                            2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               637  Cl          2,6-diF-phenyl                                                                            4-morpholinocarbonyl                               638  Cl          2,6-diF-phenyl                                                                            2-methyl-1-imidazolyl                              639  Cl          2,6-diF-phenyl                                                                            5-methyl-1-imidazolyl                              640  Cl          2,6-diF-phenyl                                                                            2-methylsulfonyl-1-imidazolyl                      641  F           phenyl     2-(aminosulfonyl)phenyl                            642  F           phenyl     2-(methylaminosulfonyl)-                                                       phenyl                                             643  F           phenyl     1-pyrrolidinocarbonyl                              644  F           phenyl     2-(methylsulfonyl)phenyl                           645  F           phenyl     4-morpholino                                       646  F           phenyl     2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               647  F           phenyl     4-morpholinocarbonyl                               648  F           phenyl     2-methyl-1-imidazolyl                              649  F           phenyl     5-methyl-1-imidazolyl                              650  F           phenyl     2-methylsulfonyl-1-imidazolyl                      651  F           2-pyridyl  2-(aminosulfonyl)phenyl                            652  F           2-pyridyl  2-(methylaminosulfonyl)-                                                       phenyl                                             653  F           2-pyridyl  1-pyrrolidinocarbonyl                              654  F           2-pyridyl  2-(methylsulfonyl)phenyl                           655  F           2-pyridyl  4-morpholino                                       656  F           2-pyridyl  2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               657  F           2-pyridyl  4-morpholinocarbonyl                               658  F           2-pyridyl  2-methyl-1-imidazolyl                              659  F           2-pyridyl  5-methyl-1-imidazolyl                              660  F           2-pyridyl  2-methylsulfonyl-1-imidazolyl                      661  F           3-pyridyl  2-(aminosulfonyl)phenyl                            662  F           3-pyridyl  2-(methylaminosulfonyl)-                                                       phenyl                                             663  F           3-pyridyl  1-pyrrolidinocarbonyl                              664  F           3-pyridyl  2-(methylsulfonyl)phenyl                           665  F           3-pyridyl  4-morpholino                                       666  F           3-pyridyl  2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               667  F           3-pyridyl  4-morpholinocarbonyl                               668  F           3-pyridyl  2-methyl-1-imidazolyl                              669  F           3-pyridyl  5-methyl-1-imidazolyl                              670  F           3-pyridyl  2-methylsulfonyl-1-imidazolyl                      671  F           2-pyrimidyl                                                                               2-(aminosulfonyl)phenyl                            672  F           2-pyrimidyl                                                                               2-(methylaminosulfonyl)-                                                       phenyl                                             673  F           2-pyrimidyl                                                                               1-pyrrolidinocarbonyl                              674  F           2-pyrimidyl                                                                               2-(methylsulfonyl)phenyl                           675  F           2-pyrimidyl                                                                               4-morpholino                                       676  F           2-pyrimidyl                                                                               2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               677  F           2-pyrimidyl                                                                               4-morpholinocarbonyl                               678  F           2-pyrimidyl                                                                               2-methyl-1-imidazolyl                              679  F           2-pyrimidyl                                                                               5-methyl-1-imidazolyl                              680  F           2-pyrimidyl                                                                               2-methylsulfonyl-1-imidazolyl                      681  F           5-pyrimidyl                                                                               2-(aminosulfonyl)phenyl                            682  F           5-pyrimidyl                                                                               2-(methylaminosulfonyl)-                                                       phenyl                                             683  F           5-pyrimidyl                                                                               1-pyrrolidinocarbonyl                              684  F           5-pyrimidyl                                                                               2-(methylsulfonyl)phenyl                           685  F           5-pyrimidyl                                                                               4-morpholino                                       686  F           5-pyrimidyl                                                                               2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               687  F           5-pyrimidyl                                                                               4-morpholinocarbonyl                               688  F           5-pyrimidyl                                                                               2-methyl-1-imidazolyl                              689  F           5-pyrimidyl                                                                               5-methyl-1-imidazolyl                              690  F           5-pyrimidyl                                                                               2-methylsulfonyl-1-imidazolyl                      691  F           2-Cl-phenyl                                                                               2-(aminosulfonyl)phenyl                            692  F           2-Cl-phenyl                                                                               2-(methylaminosulfonyl)-                                                       phenyl                                             693  F           2-Cl-phenyl                                                                               1-pyrrolidinocarbonyl                              694  F           2-Cl-phenyl                                                                               2-(methylsulfonyl)phenyl                           695  F           2-Cl-phenyl                                                                               4-morpholino                                       696  F           2-Cl-phenyl                                                                               2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               697  F           2-Cl-phenyl                                                                               4-morpholinocarbonyl                               698  F           2-Cl-phenyl                                                                               2-methyl-1-imidazolyl                              699  F           2-Cl-phenyl                                                                               5-methyl-1-imidazolyl                              700  F           2-Cl-phenyl                                                                               2-methylsulfonyl-1-imidazolyl                      701  F           2-F-phenyl 2-(aminosulfonyl)phenyl                            702  F           2-F-phenyl 2-(methylaminosulfonyl)-                                                       phenyl                                             703  F           2-F-phenyl 1-pyrrolidinocarbonyl                              704  F           2-F-phenyl 2-(methylsulfonyl)phenyl                           705  F           2-F-phenyl 4-morpholino                                       706  F           2-F-phenyl 2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               707  F           2-F-phenyl 4-morpholinocarbonyl                               708  F           2-F-phenyl 2-methyl-1-imidazolyl                              709  F           2-F-phenyl 5-methyl-1-imidazolyl                              710  F           2-F-phenyl 2-methylsulfonyl-1-imidazolyl                      711  F           2,6-diF-phenyl                                                                            2-(aminosulfonyl)phenyl                            712  F           2,6-diF-phenyl                                                                            2-(methylaminosulfonyl)-                                                       phenyl                                             713  F           2,6-diF-phenyl                                                                            1-pyrrolidinocarbonyl                              714  F           2,6-diF-phenyl                                                                            2-(methylsulfonyl)phenyl                           715  F           2,6-diF-phenyl                                                                            4-morpholino                                       716  F           2,6-diF-phenyl                                                                            2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               717  F           2,6-diF-phenyl                                                                            4-morpholinocarbonyl                               718  F           2,6-diF-phenyl                                                                            2-methyl-1-imidazolyl                              719  F           2,6-diF-phenyl                                                                            5-methyl-1-imidazolyl                              720  F           2,6-diF-phenyl                                                                            2-methylsulfonyl-1-imidazolyl                      721  CO.sub.2 CH.sub.3                                                                          phenyl     2-(aminosulfonyl)phenyl                            722  CO.sub.2 CH.sub.3                                                                          phenyl     2-(methylaminosulfonyl)-                                                       phenyl                                             723  CO.sub.2 CH.sub.3                                                                          phenyl     1-pyrrolidinocarbonyl                              724  CO.sub.2 CH.sub.3                                                                          phenyl     2-(methylsulfonyl)phenyl                           725  CO.sub.2 CH.sub.3                                                                          phenyl     4-morpholino                                       726  CO.sub.2 CH.sub.3                                                                          phenyl     2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               727  CO.sub.2 CH.sub.3                                                                          phenyl     4-morpholinocarbonyl                               728  CO.sub.2 CH.sub.3                                                                          phenyl     2-methyl-1-imidazolyl                              729  CO.sub.2 CH.sub.3                                                                          phenyl     5-methyl-1-imidazolyl                              730  CO.sub.2 CH.sub.3                                                                          phenyl     2-methylsulfonyl-1-imidazolyl                      731  CO.sub.2 CH.sub.3                                                                          2-pyridyl  2-(aminosulfonyl)phenyl                            732  CO.sub.2 CH.sub.3                                                                          2-pyridyl  2-(methylaminosulfonyl)-                                                       phenyl                                             733  CO.sub.2 CH.sub.3                                                                          2-pyridyl  1-pyrrolidinocarbonyl                              734  CO.sub.2 CH.sub.3                                                                          2-pyridyl  2-(methylsulfonyl)phenyl                           735  CO.sub.2 CH.sub.3                                                                          2-pyridyl  4-morpholino                                       736  CO.sub.2 CH.sub.3                                                                          2-pyridyl  2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               737  CO.sub.2 CH.sub.3                                                                          2-pyridyl  4-morpholinocarbonyl                               738  CO.sub.2 CH.sub.3                                                                          2-pyridyl  2-methyl-1-imidazolyl                              739  CO.sub.2 CH.sub.3                                                                          2-pyridyl  5-methyl-1-imidazolyl                              740  CO.sub.2 CH.sub.3                                                                          2-pyridyl  2-methylsulfonyl-1-imidazolyl                      741  CO.sub.2 CH.sub.3                                                                          3-pyridyl  2-(aminosulfonyl)phenyl                            742  CO.sub.2 CH.sub.3                                                                          3-pyridyl  2-(methylaminosulfonyl)-                                                       phenyl                                             743  CO.sub.2 CH.sub.3                                                                          3-pyridyl  1-pyrrolidinocarbonyl                              744  CO.sub.2 CH.sub.3                                                                          3-pyridyl  2-(methylsulfonyl)phenyl                           745  CO.sub.2 CH.sub.3                                                                          3-pyridyl  4-morpholino                                       746  CO.sub.2 CH.sub.3                                                                          3-pyridyl  2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               747  CO.sub.2 CH.sub.3                                                                          3-pyridyl  4-morpholinocarbonyl                               748  CO.sub.2 CH.sub.3                                                                          3-pyridyl  2-methyl-1-imidazolyl                              749  CO.sub.2 CH.sub.3                                                                          3-pyridyl  5-methyl-1-imidazolyl                              750  CO.sub.2 CH.sub.3                                                                          3-pyridyl  2-methylsulfonyl-1-imidazolyl                      751  CO.sub.2 CH.sub.3                                                                          2-pyrimidyl                                                                               2-(aminosulfonyl)phenyl                            752  CO.sub.2 CH.sub.3                                                                          2-pyrimidyl                                                                               2-(methylaminosulfonyl)-                                                       phenyl                                             753  CO.sub.2 CH.sub.3                                                                          2-pyrimidyl                                                                               1-pyrrolidinocarbonyl                              754  CO.sub.2 CH.sub.3                                                                          2-pyrimidyl                                                                               2-(methylsulfonyl)phenyl                           755  CO.sub.2 CH.sub.3                                                                          2-pyrimidyl                                                                               4-morpholino                                       756  CO.sub.2 CH.sub.3                                                                          2-pyrimidyl                                                                               2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               757  CO.sub.2 CH.sub.3                                                                          2-pyrimidyl                                                                               4-morpholinocarbonyl                               758  CO.sub.2 CH.sub.3                                                                          2-pyrimidyl                                                                               2-methyl-1-imidazolyl                              759  CO.sub.2 CH.sub.3                                                                          2-pyrimidyl                                                                               5-methyl-1-imidazolyl                              760  CO.sub.2 CH.sub.3                                                                          2-pyrimidyl                                                                               2-methylsulfonyl-1-imidazolyl                      761  CO.sub.2 CH.sub.3                                                                          5-pyrimidyl                                                                               2-(aminosulfonyl)phenyl                            762  CO.sub.2 CH.sub.3                                                                          5-pyrimidyl                                                                               2-(methylaminosulfonyl)-                                                       phenyl                                             763  CO.sub.2 CH.sub.3                                                                          5-pyrimidyl                                                                               1-pyrrolidinocarbonyl                              764  CO.sub.2 CH.sub.3                                                                          5-pyrimidyl                                                                               2-(methylsulfonyl)phenyl                           765  CO.sub.2 CH.sub.3                                                                          5-pyrimidyl                                                                               4-morpholino                                       766  CO.sub.2 CH.sub.3                                                                          5-pyrimidyl                                                                               2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               767  CO.sub.2 CH.sub.3                                                                          5-pyrimidyl                                                                               4-morpholinocarbonyl                               768  CO.sub.2 CH.sub.3                                                                          5-pyrimidyl                                                                               2-methyl-1-imidazolyl                              769  CO.sub.2 CH.sub.3                                                                          5-pyrimidyl                                                                               5-methyl-1-imidazolyl                              770  CO.sub.2 CH.sub.3                                                                          5-pyrimidyl                                                                               2-methylsulfonyl-1-imidazolyl                      771  CO.sub.2 CH.sub.3                                                                          2-Cl-phenyl                                                                               2-(aminosulfonyl)phenyl                            772  CO.sub.2 CH.sub.3                                                                          2-Cl-phenyl                                                                               2-(methylaminosulfonyl)-                                                       phenyl                                             773  CO.sub.2 CH.sub.3                                                                          2-Cl-phenyl                                                                               1-pyrrolidinocarbonyl                              774  CO.sub.2 CH.sub.3                                                                          2-Cl-phenyl                                                                               2-(methylsulfonyl)phenyl                           775  CO.sub.2 CH.sub.3                                                                          2-Cl-phenyl                                                                               4-morpholino                                       776  CO.sub.2 CH.sub.3                                                                          2-Cl-phenyl                                                                               2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               777  CO.sub.2 CH.sub.3                                                                          2-Cl-phenyl                                                                               4-morpholinocarbonyl                               778  CO.sub.2 CH.sub.3                                                                          2-Cl-phenyl                                                                               2-methyl-1-imidazolyl                              779  CO.sub.2 CH.sub.3                                                                          2-Cl-phenyl                                                                               5-methyl-1-imidazolyl                              780  CO.sub.2 CH.sub.3                                                                          2-Cl-phenyl                                                                               2-methylsulfonyl-1-imidazolyl                      781  CO.sub.2 CH.sub.3                                                                          2-F-phenyl 2-(aminosulfonyl)phenyl                            782  CO.sub.2 CH.sub.3                                                                          2-F-phenyl 2-(methylaminosulfonyl)-                                                       phenyl                                             783  CO.sub.2 CH.sub.3                                                                          2-F-phenyl 1-pyrrolidinocarbonyl                              784  CO.sub.2 CH.sub.3                                                                          2-F-phenyl 2-(methylsulfonyl)phenyl                           785  CO.sub.2 CH.sub.3                                                                          2-F-phenyl 4-morpholino                                       786  CO.sub.2 CH.sub.3                                                                          2-F-phenyl 2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               787  CO.sub.2 CH.sub.3                                                                          2-F-phenyl 4-morpholinocarbonyl                               788  CO.sub.2 CH.sub.3                                                                          2-F-phenyl 2-methyl-1-imidazolyl                              789  CO.sub.2 CH.sub.3                                                                          2-F-phenyl 5-methyl-1-imidazolyl                              790  CO.sub.2 CH.sub.3                                                                          2-F-phenyl 2-methylsulfonyl-1-imidazolyl                      791  CO.sub.2 CH.sub.3                                                                          2,6-diF-phenyl                                                                            2-(aminosulfonyl)phenyl                            792  CO.sub.2 CH.sub.3                                                                          2,6-diF-phenyl                                                                            2-(methylaminosulfonyl)-                                                       phenyl                                             793  CO.sub.2 CH.sub.3                                                                          2,6-diF-phenyl                                                                            1-pyrrolidinocarbonyl                              794  CO.sub.2 CH.sub.3                                                                          2,6-diF-phenyl                                                                            2-(methylsulfonyl)phenyl                           795  CO.sub.2 CH.sub.3                                                                          2,6-diF-phenyl                                                                            4-morpholino                                       796  CO.sub.2 CH.sub.3                                                                          2,6-diF-phenyl                                                                            2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               797  CO.sub.2 CH.sub.3                                                                          2,6-diF-phenyl                                                                            4-morpholinocarbonyl                               798  CO.sub.2 CH.sub.3                                                                          2,6-diF-phenyl                                                                            2-methyl-1-imidazolyl                              799  CO.sub.2 CH.sub.3                                                                          2,6-diF-phenyl                                                                            5-methyl-1-imidazolyl                              800  CO.sub.2 CH.sub.3                                                                          2,6-diF-phenyl                                                                            2-methylsulfonyl-1-imidazolyl                      801  CH.sub.2 OCH.sub.3                                                                         phenyl     2-(aminosulfonyl)phenyl                            802  CH.sub.2 OCH.sub.3                                                                         phenyl     2-(methylaminosulfonyl)-                                                       phenyl                                             803  CH.sub.2 OCH.sub.3                                                                         phenyl     1-pyrrolidinocarbonyl                              804  CH.sub.2 OCH.sub.3                                                                         phenyl     2-(methylsulfonyl)phenyl                           805  CH.sub.2 OCH.sub.3                                                                         phenyl     4-morpholino                                       806  CH.sub.2 OCH.sub.3                                                                         phenyl     2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               807  CH.sub.2 OCH.sub.3                                                                         phenyl     4-morpholinocarbonyl                               808  CH.sub.2 OCH.sub.3                                                                         phenyl     2-methyl-1-imidazolyl                              809  CH.sub.2 OCH.sub.3                                                                         phenyl     5-methyl-1-imidazolyl                              810  CH.sub.2 OCH.sub.3                                                                         phenyl     2-methylsulfonyl-1-imidazolyl                      811  CH.sub.2 OCH.sub.3                                                                         2-pyridyl  2-(aminosulfonyl)phenyl                            812  CH.sub.2 OCH.sub.3                                                                         2-pyridyl  2-(methylaminosulfonyl)-                                                       phenyl                                             813  CH.sub.2 OCH.sub.3                                                                         2-pyridyl  1-pyrrolidinocarbonyl                              814  CH.sub.2 OCH.sub.3                                                                         2-pyridyl  2-(methylsulfonyl)phenyl                           815  CH.sub.2 OCH.sub.3                                                                         2-pyridyl  4-morpholino                                       816  CH.sub.2 OCH.sub.3                                                                         2-pyridyl  2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               817  CH.sub.2 OCH.sub.3                                                                         2-pyridyl  4-morpholinocarbonyl                               818  CH.sub.2 OCH.sub.3                                                                         2-pyridyl  2-methyl-1-imidazolyl                              819  CH.sub.2 OCH.sub.3                                                                         2-pyridyl  5-methyl-1-imidazolyl                              820  CH.sub.2 OCH.sub.3                                                                         2-pyridyl  2-methylsulfonyl-1-imidazolyl                      821  CH.sub.2 OCH.sub.3                                                                         3-pyridyl  2-(aminosulfonyl)phenyl                            822  CH.sub.2 OCH.sub.3                                                                         3-pyridyl  2-(methylaminosulfonyl)-                                                       phenyl                                             823  CH.sub.2 OCH.sub.3                                                                         3-pyridyl  1-pyrrolidinocarbonyl                              824  CH.sub.2 OCH.sub.3                                                                         3-pyridyl  2-(methylsulfonyl)phenyl                           825  CH.sub.2 OCH.sub.3                                                                         3-pyridyl  4-morpholino                                       826  CH.sub.2 OCH.sub.3                                                                         3-pyridyl  2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               827  CH.sub.2 OCH.sub.3                                                                         3-pyridyl  4-morpholinocarbonyl                               828  CH.sub.2 OCH.sub.3                                                                         3-pyridyl  2-methyl-1-imidazolyl                              829  CH.sub.2 OCH.sub.3                                                                         3-pyridyl  5-methyl-1-imidazolyl                              830  CH.sub.2 OCH.sub.3                                                                         3-pyridyl  2-methylsulfonyl-1-imidazolyl                      831  CH.sub.2 OCH.sub.3                                                                         2-pyrimidyl                                                                               2-(aminosulfonyl)phenyl                            832  CH.sub.2 OCH.sub.3                                                                         2-pyrimidyl                                                                               2-(methylaminosulfonyl)-                                                       phenyl                                             833  CH.sub.2 OCH.sub.3                                                                         2-pyrimidyl                                                                               1-pyrrolidinocarbonyl                              834  CH.sub.2 OCH.sub.3                                                                         2-pyrimidyl                                                                               2-(methylsulfonyl)phenyl                           835  CH.sub.2 OCH.sub.3                                                                         2-pyrimidyl                                                                               4-morpholino                                       836  CH.sub.2 OCH.sub.3                                                                         2-pyrimidyl                                                                               2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               837  CH.sub.2 OCH.sub.3                                                                         2-pyrimidyl                                                                               4-morpholinocarbonyl                               838  CH.sub.2 OCH.sub.3                                                                         2-pyrimidyl                                                                               2-methyl-1-imidazolyl                              839  CH.sub.2 OCH.sub.3                                                                         2-pyrimidyl                                                                               5-methyl-1-imidazolyl                              840  CH.sub.2 OCH.sub.3                                                                         2-pyrimidyl                                                                               2-methylsulfonyl-1-imidazolyl                      841  CH.sub.2 OCH.sub.3                                                                         5-pyrimidyl                                                                               2-(aminosulfonyl)phenyl                            842  CH.sub.2 OCH.sub.3                                                                         5-pyrimidyl                                                                               2-(methylaminosulfonyl)-                                                       phenyl                                             843  CH.sub.2 OCH.sub.3                                                                         5-pyrimidyl                                                                               1-pyrrolidinocarbonyl                              844  CH.sub.2 OCH.sub.3                                                                         5-pyrimidyl                                                                               2-(methylsulfonyl)phenyl                           845  CH.sub.2 OCH.sub.3                                                                         5-pyrimidyl                                                                               4-morpholino                                       846  CH.sub.2 OCH.sub.3                                                                         5-pyrimidyl                                                                               2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               847  CH.sub.2 OCH.sub.3                                                                         5-pyrimidyl                                                                               4-morpholinocarbonyl                               848  CH.sub.2 OCH.sub.3                                                                         5-pyrimidyl                                                                               2-methyl-1-imidazolyl                              849  CH.sub.2 OCH.sub.3                                                                         5-pyrimidyl                                                                               5-methyl-1-imidazolyl                              850  CH.sub.2 OCH.sub.3                                                                         5-pyrimidyl                                                                               2-methylsulfonyl-1-imidazolyl                      851  CH.sub.2 OCH.sub.3                                                                         2-Cl-phenyl                                                                               2-(aminosulfonyl)phenyl                            852  CH.sub.2 OCH.sub.3                                                                         2-Cl-phenyl                                                                               2-(methylaminosulfonyl)-                                                       phenyl                                             853  CH.sub.2 OCH.sub.3                                                                         2-Cl-phenyl                                                                               1-pyrrolidinocarbonyl                              854  CH.sub.2 OCH.sub.3                                                                         2-Cl-phenyl                                                                               2-(methylsulfonyl)phenyl                           855  CH.sub.2 OCH.sub.3                                                                         2-Cl-phenyl                                                                               4-morpholino                                       856  CH.sub.2 OCH.sub.3                                                                         2-Cl-phenyl                                                                               2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               857  CH.sub.2 OCH.sub.3                                                                         2-Cl-phenyl                                                                               4-morpholinocarbonyl                               858  CH.sub.2 OCH.sub.3                                                                         2-Cl-phenyl                                                                               2-methyl-1-imidazolyl                              859  CH.sub.2 OCH.sub.3                                                                         2-Cl-phenyl                                                                               5-methyl-1-imidazolyl                              860  CH.sub.2 OCH.sub.3                                                                         2-Cl-phenyl                                                                               2-methylsulfonyl-1-imidazolyl                      861  CH.sub.2 OCH.sub.3                                                                         2-F-phenyl 2-(aminosulfonyl)phenyl                            862  CH.sub.2 OCH.sub.3                                                                         2-F-phenyl 2-(methylaminosulfonyl)-                                                       phenyl                                             863  CH.sub.2 OCH.sub.3                                                                         2-F-phenyl 1-pyrrolidinocarbonyl                              864  CH.sub.2 OCH.sub.3                                                                         2-F-phenyl 2-(methylsulfonyl)phenyl                           865  CH.sub.2 OCH.sub.3                                                                         2-F-phenyl 4-morpholino                                       866  CH.sub.2 OCH.sub.3                                                                         2-F-phenyl 2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               867  CH.sub.2 OCH.sub.3                                                                         2-F-phenyl 4-morpholinocarbonyl                               868  CH.sub.2 OCH.sub.3                                                                         2-F-phenyl 2-methyl-1-imidazolyl                              869  CH.sub.2 OCH.sub.3                                                                         2-F-phenyl 5-methyl-1-imidazolyl                              870  CH.sub.2 OCH.sub.3                                                                         2-F-phenyl 2-methylsulfonyl-1-imidazolyl                      871  CH.sub.2 OCH.sub.3                                                                         2,6-diF-phenyl                                                                            2-(aminosulfonyl)phenyl                            872  CH.sub.2 OCH.sub.3                                                                         2,6-diF-phenyl                                                                            2-(methylaminosulfonyl)-                                                       phenyl                                             873  CH.sub.2 OCH.sub.3                                                                         2,6-diF-phenyl                                                                            1-pyrrolidinocarbonyl                              874  CH.sub.2 OCH.sub.3                                                                         2,6-diF-phenyl                                                                            2-(methylsulfonyl)phenyl                           875  CH.sub.2 OCH.sub.3                                                                         2,6-diF-phenyl                                                                            4-morpholino                                       876  CH.sub.2 OCH.sub.3                                                                         2,6-diF-phenyl                                                                            2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               877  CH.sub.2 OCH.sub.3                                                                         2,6-diF-phenyl                                                                            4-morpholinocarbonyl                               878  CH.sub.2 OCH.sub.3                                                                         2,6-diF-phenyl                                                                            2-methyl-1-imidazolyl                              879  CH.sub.2 OCH.sub.3                                                                         2,6-diF-phenyl                                                                            5-methyl-1-imidazolyl                              880  CH.sub.2 OCH.sub.3                                                                         2,6-diF-phenyl                                                                            2-methylsulfonyl-1-imidazolyl                      881  CONH.sub.2  phenyl     2-(aminosulfonyl)phenyl                            882  CONH.sub.2  phenyl     2-(methylaminosulfonyl)-                                                       phenyl                                             883  CONH.sub.2  phenyl     1-pyrrolidinocarbonyl                              884  CONH.sub.2  phenyl     2-(methylsulfonyl)phenyl                           885  CONH.sub.2  phenyl     4-morpholino                                       886  CONH.sub.2  phenyl     2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               887  CONH.sub.2  phenyl     4-morpholinocarbonyl                               888  CONH.sub.2  phenyl     2-methyl-1-imidazolyl                              889  CONH.sub.2  phenyl     5-methyl-1-imidazolyl                              890  CONH.sub.2  phenyl     2-methylsulfonyl-1-imidazolyl                      891  CONH.sub.2  2-pyridyl  2-(aminosulfonyl)phenyl                            892  CONH.sub.2  2-pyridyl  2-(methylaminosulfonyl)-                                                       phenyl                                             893  CONH.sub.2  2-pyridyl  1-pyrrolidinocarbonyl                              894  CONH.sub.2  2-pyridyl  2-(methylsulfonyl)phenyl                           895  CONH.sub.2  2-pyridyl  4-morpholino                                       896  CONH.sub.2  2-pyridyl  2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               897  CONH.sub.2  2-pyridyl  4-morpholinocarbonyl                               898  CONH.sub.2  2-pyridyl  2-methyl-1-imidazolyl                              899  CONH.sub.2  2-pyridyl  5-methyl-1-imidazolyl                              900  CONH.sub.2  2-pyridyl  2-methylsulfonyl-1-imidazolyl                      901  CONH.sub.2  3-pyridyl  2-(aminosulfonyl)phenyl                            902  CONH.sub.2  3-pyridyl  2-(methylaminosulfonyl)-                                                       phenyl                                             903  CONH.sub.2  3-pyridyl  1-pyrrolidinocarbonyl                              904  CONH.sub.2  3-pyridyl  2-(methylsulfonyl)phenyl                           905  CONH.sub.2  3-pyridyl  4-morpholino                                       906  CONH.sub.2  3-pyridyl  2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               907  CONH.sub.2  3-pyridyl  4-morpholinocarbonyl                               908  CONH.sub.2  3-pyridyl  2-methyl-1-imidazolyl                              909  CONH.sub.2  3-pyridyl  5-methyl-1-imidazolyl                              910  CONH.sub.2  3-pyridyl  2-methylsulfonyl-1-imidazolyl                      911  CONH.sub.2  2-pyrimidyl                                                                               2-(aminosulfonyl)phenyl                            912  CONH.sub.2  2-pyrimidyl                                                                               2-(methylaminosulfonyl)-                                                       phenyl                                             913  CONH.sub.2  2-pyrimidyl                                                                               1-pyrrolidinocarbonyl                              914  CONH.sub.2  2-pyrimidyl                                                                               2-(methylsulfonyl)phenyl                           915  CONH.sub.2  2-pyrimidyl                                                                               4-morpholino                                       916  CONH.sub.2  2-pyrimidyl                                                                               2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               917  CONH.sub.2  2-pyrimidyl                                                                               4-morpholinocarbonyl                               918  CONH.sub.2  2-pyrimidyl                                                                               2-methyl-1-imidazolyl                              919  CONH.sub.2  2-pyrimidyl                                                                               5-methyl-1-imidazolyl                              920  CONH.sub.2  2-pyrimidyl                                                                               2-methylsulfonyl-1-imidazolyl                      921  CONH.sub.2  5-pyrimidyl                                                                               2-(aminosulfonyl)phenyl                            922  CONH.sub.2  5-pyrimidyl                                                                               2-(methylaminosulfonyl)-                                                       phenyl                                             923  CONH.sub.2  5-pyrimidyl                                                                               1-pyrrolidinocarbonyl                              924  CONH.sub.2  5-pyrimidyl                                                                               2-(methylsulfonyl)phenyl                           925  CONH.sub.2  5-pyrimidyl                                                                               4-morpholino                                       926  CONH.sub.2  5-pyrimidyl                                                                               2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               927  CONH.sub.2  5-pyrimidyl                                                                               4-morpholinocarbonyl                               928  CONH.sub.2  5-pyrimidyl                                                                               2-methyl-1-imidazolyl                              929  CONH.sub.2  5-pyrimidyl                                                                               5-methyl-1-imidazolyl                              930  CONH.sub.2  5-pyrimidyl                                                                               2-methylsulfonyl-1-imidazolyl                      931  CONH.sub.2  2-Cl-phenyl                                                                               2-(aminosulfonyl)phenyl                            932  CONH.sub.2  2-Cl-phenyl                                                                               2-(methylaminosulfonyl)-                                                       phenyl                                             933  CONH.sub.2  2-Cl-phenyl                                                                               1-pyrrolidinocarbonyl                              934  CONH.sub.2  2-Cl-phenyl                                                                               2-(methylsulfonyl)phenyl                           935  CONH.sub.2  2-Cl-phenyl                                                                               4-morpholino                                       936  CONH.sub.2  2-Cl-phenyl                                                                               2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               937  CONH.sub.2  2-Cl-phenyl                                                                               4-morpholinocarbonyl                               938  CONH.sub.2  2-Cl-phenyl                                                                               2-methyl-1-imidazolyl                              939  CONH.sub.2  2-Cl-phenyl                                                                               5-methyl-1-imidazolyl                              940  CONH.sub.2  2-Cl-phenyl                                                                               2-methylsulfonyl-1-imidazolyl                      941  CONH.sub.2  2-F-phenyl 2-(aminosulfonyl)phenyl                            942  CONH.sub.2  2-F-phenyl 2-(methylaminosulfonyl)-                                                       phenyl                                             943  CONH.sub.2  2-F-phenyl 1-pyrrolidinocarbonyl                              944  CONH.sub.2  2-F-phenyl 2-(methylsulfonyl)phenyl                           945  CONH.sub.2  2-F-phenyl 4-morpholino                                       946  CONH.sub.2  2-F-phenyl 2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               947  CONH.sub.2  2-F-phenyl 4-morpholinocarbonyl                               948  CONH.sub.2  2-F-phenyl 2-methyl-1-imidazolyl                              949  CONH.sub.2  2-F-phenyl 5-methyl-1-imidazolyl                              950  CONH.sub.2  2-F-phenyl 2-methylsulfonyl-1-imidazolyl                      951  CONH.sub.2  2,6-diF-phenyl                                                                            2-(aminosulfonyl)phenyl                            952  CONH.sub.2  2,6-diF-phenyl                                                                            2-(methylaminosulfonyl)-                                                       phenyl                                             953  CONH.sub.2  2,6-diF-phenyl                                                                            1-pyrrolidinocarbonyl                              954  CONH.sub.2  2,6-diF-phenyl                                                                            2-(methylsulfonyl)phenyl                           955  CONH.sub.2  2,6-diF-phenyl                                                                            4-morpholino                                       956  CONH.sub.2  2,6-diF-phenyl                                                                            2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl               957  CONH.sub.2  2,6-diF-phenyl                                                                            4-morpholinocarbonyl                               958  CONH.sub.2  2,6-diF-phenyl                                                                            2-methyl-1-imidazolyl                              959  CONH.sub.2  2,6-diF-phenyl                                                                            5-methyl-1-imidazolyl                              960  CONH.sub.2  2,6-diF-phenyl                                                                            2-methylsulfonyl-1-imidazolyl                      ______________________________________                                    

                  TABLE 5                                                          ______________________________________                                          ##STR212##                                                                     ##STR213##                                                                    Ex #    A            B                                                         ______________________________________                                          1      phenyl       2-(aminosulfonyl)phenyl                                    2      phenyl       2-(methylaminosulfonyl)phenyl                              3      phenyl       1-pyrrolidinocarbonyl                                      4      phenyl       2-(methylsulfonyl)phenyl                                   5      phenyl       4-morpholino                                               6      phenyl       2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                       7      phenyl       4-morpholinocarbonyl                                       8      phenyl       2-methyl-1-imidazolyl                                      9      phenyl       5-methyl-1-imidazolyl                                     10      phenyl       2-methylsulfonyl-1-imidazolyl                             11      2-pyridyl    2-(aminosulfonyl)phenyl                                   12      2-pyridyl    2-(methylaminosulfonyl)phenyl                             13      2-pyridyl    1-pyrrolidinocarbonyl                                     14      2-pyridyl    2-(methylsulfonyl)phenyl                                  15      2-pyridyl    4-morpholino                                              16      2-pyridyl    2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                      17      2-pyridyl    4-morpholinocarbonyl                                      18      2-pyridyl    2-methyl-1-imidazolyl                                     19      2-pyridyl    5-methyl-1-imidazolyl                                     20      2-pyridyl    2-methylsulfonyl-1-imidazolyl                             21      3-pyridyl    2-(aminosulfonyl)phenyl                                   22      3-pyridyl    2-(methylaminosulfonyl)phenyl                             23      3-pyridyl    1-pyrrolidinocarbonyl                                     24      3-pyridyl    2-(methylsulfonyl)phenyl                                  25      3-pyridyl    4-morpholino                                              26      3-pyridyl    2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                      27      3-pyridyl    4-morpholinocarbonyl                                      28      3-pyridyl    2-methyl-1-imidazolyl                                     29      3-pyridyl    5-methyl-1-imidazolyl                                     30      3-pyridyl    2-methylsulfonyl-1-imidazolyl                             31      2-pyrimidyl  2-(aminosulfonyl)phenyl                                   32      2-pyrimidyl  2-(methylaminosulfonyl)phenyl                             33      2-pyrimidyl  1-pyrrolidinocarbonyl                                     34      2-pyrimidyl  2-(methylsulfonyl)phenyl                                  35      2-pyrimidyl  4-morpholino                                              36      2-pyrimidyl  2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                      37      2-pyrimidyl  4-morpholinocarbonyl                                      38      2-pyrimidyl  2-methyl-1-imidazolyl                                     39      2-pyrimidyl  5-methyl-1-imidazolyl                                     40      2-pyrimidyl  2-methylsulfonyl-1-imidazolyl                             41      5-pyrimidyl  2-(aminosulfonyl)phenyl                                   42      5-pyrimidyl  2-(methylaminosulfonyl)phenyl                             43      5-pyrimidyl  1-pyrrolidinocarbonyl                                     44      5-pyrimidyl  2-(methylsulfonyl)phenyl                                  45      5-pyrimidyl  4-morpholino                                              46      5-pyrimidyl  2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                      47      5-pyrimidyl  4-morpholinocarbonyl                                      48      5-pyrimidyl  2-methyl-1-imidazolyl                                     49      5-pyrimidyl  5-methyl-1-imidazolyl                                     50      5-pyrimidyl  2-methylsulfonyl-1-imidazolyl                             51      2-Cl-phenyl  2-(aminosulfonyl)phenyl                                   52      2-Cl-phenyl  2-(methylaminosulfonyl)phenyl                             53      2-Cl-phenyl  1-pyrrolidinocarbonyl                                     54      2-Cl-phenyl  2-(methylsulfonyl)phenyl                                  55      2-Cl-phenyl  4-morpholino                                              56      2-Cl-phenyl  2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                      57      2-Cl-phenyl  4-morpholinocarbonyl                                      58      2-Cl-phenyl  2-methyl-1-imidazolyl                                     59      2-Cl-phenyl  5-methyl-1-imidazolyl                                     60      2-Cl-phenyl  2-methylsulfonyl-1-imidazolyl                             61      2-F-phenyl   2-(aminosulfonyl)phenyl                                   62      2-F-phenyl   2-(methylaminosulfonyl)phenyl                             63      2-F-phenyl   1-pyrrolidinocarbonyl                                     64      2-F-phenyl   2-(methylsulfonyl)phenyl                                  65      2-F-phenyl   4-morpholino                                              66      2-F-phenyl   2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                      67      2-F-phenyl   4-morpholinocarbonyl                                      68      2-F-phenyl   2-methyl-1-imidazolyl                                     69      2-F-phenyl   5-methyl-1-imidazolyl                                     70      2-F-phenyl   2-methylsulfonyl-1-imidazolyl                             71      2,6-diF-phenyl                                                                              2-(aminosulfonyl)phenyl                                   72      2,6-diF-phenyl                                                                              2-(methylaminosulfonyl)phenyl                             73      2,6-diF-phenyl                                                                              1-pyrrolidinocarbonyl                                     74      2,6-diF-phenyl                                                                              2-(methylsulfonyl)phenyl                                  75      2,6-diF-phenyl                                                                              4-morpholino                                              76      2,6-diF-phenyl                                                                              2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                      77      2,6-diF-phenyl                                                                              4-morpholinocarbonyl                                      78      2,6-diF-phenyl                                                                              2-methyl-1-imidazolyl                                     79      2,6-diF-phenyl                                                                              5-methyl-1-imidazolyl                                     80      2,6-diF-phenyl                                                                              2-methylsulfonyl-1-imidazolyl                             ______________________________________                                    

                  TABLE 6                                                          ______________________________________                                          ##STR214##                                                                     ##STR215##                                                                     ##STR216##                                                                     ##STR217##                                                                     ##STR218##                                                                     ##STR219##                                                                     ##STR220##                                                                     ##STR221##                                                                     ##STR222##                                                                     ##STR223##                                                                     ##STR224##                                                                     ##STR225##                                                                     ##STR226##                                                                     ##STR227##                                                                     ##STR228##                                                                     ##STR229##                                                                     ##STR230##                                                                     ##STR231##                                                                     ##STR232##                                                                     ##STR233##                                                                     ##STR234##                                                                     ##STR235##                                                                     ##STR236##                                                                     ##STR237##                                                                     ##STR238##                                                                     ##STR239##                                                                     ##STR240##                                                                     ##STR241##                                                                     ##STR242##                                                                     ##STR243##                                                                     ##STR244##                                                                     ##STR245##                                                                     ##STR246##                                                                     ##STR247##                                                                     ##STR248##                                                                     ##STR249##                                                                     ##STR250##                                                                     ##STR251##                                                                     ##STR252##                                                                     ##STR253##                                                                     ##STR254##                                                                     ##STR255##                                                                     ##STR256##                                                                     ##STR257##                                                                     ##STR258##                                                                     ##STR259##                                                                     ##STR260##                                                                     ##STR261##                                                                     ##STR262##                                                                    Ex # R.sup.1a    A         B                                                   ______________________________________                                         1     CH.sub.3    phenyl   2-(aminosulfonyl)phenyl                             2    CH.sub.3    phenyl    2-(methylaminosulfonyl)phenyl                       3    CH.sub.3    phenyl    1-pyrrolidinocarbonyl                               4    CH.sub.3    phenyl    2-(methylsulfonyl)phenyl                            5    CH.sub.3    phenyl    4-morpholino                                        6    CH.sub.3    phenyl    2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                7    CH.sub.3    phenyl    4-morpholinocarbonyl                                8    CH.sub.3    phenyl    2-methyl-1-imidazolyl                               9    CH.sub.3    phenyl    5-methyl-1-imidazolyl                               10   CH.sub.3    phenyl    2-methylsulfonyl-1-imidazolyl                       11   CH.sub.3    2-pyridyl 2-(aminosulfonyl)phenyl                             12   CH.sub.3    2-pyridyl 2-(methylaminosulfonyl)phenyl                       13   CH.sub.3    2-pyridyl 1-pyrrolidinocarbonyl                               14   CH.sub.3    2-pyridyl 2-(methylsulfonyl)phenyl                            15   CH.sub.3    2-pyridyl 4-morpholino                                        16   CH.sub.3    2-pyridyl 2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                17   CH.sub.3    2-pyridyl 4-morpholinocarbonyl                                18   CH.sub.3    2-pyridyl 2-methyl-1-imidazolyl                               19   CH.sub.3    2-pyridyl 5-methyl-1-imidazolyl                               20   CH.sub.3    2-pyridyl 2-methylsulfonyl-1-imidazolyl                       21   CH.sub.3    3-pyridyl 2-(aminosulfonyl)phenyl                             22   CH.sub.3    3-pyridyl 2-(methylaminosulfonyl)phenyl                       23   CH.sub.3    3-pyridyl 1-pyrrolidinocarbonyl                               24   CH.sub.3    3-pyridyl 2-(methylsulfonyl)phenyl                            25   CH.sub.3    3-pyridyl 4-morpholino                                        26   CH.sub.3    3-pyridyl 2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                27   CH.sub.3    3-pyridyl 4-morpholinocarbonyl                                28   CH.sub.3    3-pyridyl 2-methyl-1-imidazolyl                               29   CH.sub.3    3-pyridyl 5-methyl-1-imidazolyl                               30   CH.sub.3    3-pyridyl 2-methylsulfonyl-1-imidazolyl                       31   CH.sub.3    2-pyrimidyl                                                                              2-(aminosulfonyl)phenyl                             32   CH.sub.3    2-pyrimidyl                                                                              2-(methylaminosulfonyl)phenyl                       33   CH.sub.3    2-pyrimidyl                                                                              1-pyrrolidinocarbonyl                               34   CH.sub.3    2-pyrimidyl                                                                              2-(methylsulfonyl)phenyl                            35   CH.sub.3    2-pyrimidyl                                                                              4-morpholino                                        36   CH.sub.3    2-pyrimidyl                                                                              2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                37   CH.sub.3    2-pyrimidyl                                                                              4-morpholinocarbonyl                                38   CH.sub.3    2-pyrimidyl                                                                              2-methyl-1-imidazolyl                               39   CH.sub.3    2-pyrimidyl                                                                              5-methyl-1-imidazolyl                               40   CH.sub.3    2-pyrimidyl                                                                              2-methylsulfonyl-1-imidazolyl                       41   CH.sub.3    5-pyrimidyl                                                                              2-(aminosulfonyl)phenyl                             42   CH.sub.3    5-pyrimidyl                                                                              2-(methylaminosulfonyl)phenyl                       43   CH.sub.3    5-pyrimidyl                                                                              1-pyrrolidinocarbonyl                               44   CH.sub.3    5-pyrimidyl                                                                              2-(methylsulfonyl)phenyl                            45   CH.sub.3    5-pyrimidyl                                                                              4-morpholino                                        46   CH.sub.3    5-pyrimidyl                                                                              2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                47   CH.sub.3    5-pyrimidyl                                                                              4-morpholinocarbonyl                                48   CH.sub.3    5-pyrimidyl                                                                              2-methyl-1-imidazolyl                               49   CH.sub.3    5-pyrimidyl                                                                              5-methyl-1-imidazolyl                               50   CH.sub.3    5-pyrimidyl                                                                              2-methylsulfonyl-1-imidazolyl                       51   CH.sub.3    2-Cl-phenyl                                                                              2-(aminosulfonyl)phenyl                             52   CH.sub.3    2-Cl-phenyl                                                                              2-(methylaminosulfonyl)phenyl                       53   CH.sub.3    2-Cl-phenyl                                                                              1-pyrrolidinocarbonyl                               54   CH.sub.3    2-Cl-phenyl                                                                              2-(methylsulfonyl)phenyl                            55   CH.sub.3    2-Cl-phenyl                                                                              4-morpholino                                        56   CH.sub.3    2-Cl-phenyl                                                                              2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                57   CH.sub.3    2-Cl-phenyl                                                                              4-morpholinocarbonyl                                58   CH.sub.3    2-Cl-phenyl                                                                              2-methyl-1-imidazolyl                               59   CH.sub.3    2-Cl-phenyl                                                                              5-methyl-1-imidazolyl                               60   CH.sub.3    2-Cl-phenyl                                                                              2-methylsulfonyl-1-imidazolyl                       61   CH.sub.3    2-F-phenyl                                                                               2-(aminosulfonyl)phenyl                             62   CH.sub.3    2-F-phenyl                                                                               2-(methylaminosulfonyl)phenyl                       63   CH.sub.3    2-F-phenyl                                                                               1-pyrrolidinocarbonyl                               64   CH.sub.3    2-F-phenyl                                                                               2-(methylsulfonyl)phenyl                            65   CH.sub.3    2-F-phenyl                                                                               4-morpholino                                        66   CH.sub.3    2-F-phenyl                                                                               2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                67   CH.sub.3    2-F-phenyl                                                                               4-morpholinocarbonyl                                68   CH.sub.3    2-F-phenyl                                                                               2-methyl-1-imidazolyl                               69   CH.sub.3    2-F-phenyl                                                                               5-methyl-1-imidazolyl                               70   CH.sub.3    2-F-phenyl                                                                               2-methylsulfonyl-1-imidazolyl                       71   CH.sub.3    2,6-diF-  2-(aminosulfonyl)phenyl                                              phenyl                                                        72   CH.sub.3    2,6-diF-  2-(methylaminosulfonyl)phenyl                                        phenyl                                                        73   CH.sub.3    2,6-diF-  1-pyrrolidinocarbonyl                                                phenyl                                                        74   CH.sub.3    2,6-diF-  2-(methylsulfonyl)phenyl                                             phenyl                                                        75   CH.sub.3    2,6-diF-  4-morpholino                                                         phenyl                                                        76   CH.sub.3    2,6-diF-  2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                                 phenyl                                                        77   CH.sub.3    2,6-diF-  4-morpholinocarbonyl                                                 phenyl                                                        78   CH.sub.3    2,6-diF-  2-methyl-1-imidazolyl                                                phenyl                                                        79   CH.sub.3    2,6-diF-  5-methyl-1-imidazolyl                                                phenyl                                                        80   CH.sub.3    2,6-diF-  2-methylsulfonyl-1-imidazolyl                                        phenyl                                                        81   CH.sub.2 CH.sub.3                                                                          phenyl    2-(aminosulfonyl)phenyl                             82   CH.sub.2 CH.sub.3                                                                          phenyl    2-(methylaminosulfonyl)phenyl                       83   CH.sub.2 CH.sub.3                                                                          phenyl    1-pyrrolidinocarbonyl                               84   CH.sub.2 CH.sub.3                                                                          phenyl    2-(methylsulfonyl)phenyl                            85   CH.sub.2 CH.sub.3                                                                          phenyl    4-morpholino                                        86   CH.sub.2 CH.sub.3                                                                          phenyl    2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                87   CH.sub.2 CH.sub.3                                                                          phenyl    4-morpholinocarbonyl                                88   CH.sub.2 CH.sub.3                                                                          phenyl    2-methyl-1-imidazolyl                               89   CH.sub.2 CH.sub.3                                                                          phenyl    5-methyl-1-imidazolyl                               90   CH.sub.2 CH.sub.3                                                                          phenyl    2-methylsulfonyl-1-imidazolyl                       91   CH.sub.2 CH.sub.3                                                                          2-pyridyl 2-(aminosulfonyl)phenyl                             92   CH.sub.2 CH.sub.3                                                                          2-pyridyl 2-(methylaminosulfonyl)phenyl                       93   CH.sub.2 CH.sub.3                                                                          2-pyridyl 1-pyrrolidinocarbonyl                               94   CH.sub.2 CH.sub.3                                                                          2-pyridyl 2-(methylsulfonyl)phenyl                            95   CH.sub.2 CH.sub.3                                                                          2-pyridyl 4-morpholino                                        96   CH.sub.2 CH.sub.3                                                                          2-pyridyl 2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                97   CH.sub.2 CH.sub.3                                                                          2-pyridyl 4-morpholinocarbonyl                                98   CH.sub.2 CH.sub.3                                                                          2-pyridyl 2-methyl-1-imidazolyl                               99   CH.sub.2 CH.sub.3                                                                          2-pyridyl 5-methyl-1-imidazolyl                               100  CH.sub.2 CH.sub.3                                                                          2-pyridyl 2-methylsulfonyl-1-imidazolyl                       101  CH.sub.2 CH.sub.3                                                                          3-pyridyl 2-(aminosulfonyl)phenyl                             102  CH.sub.2 CH.sub.3                                                                          3-pyridyl 2-(methylaminosulfonyl)phenyl                       103  CH.sub.2 CH.sub.3                                                                          3-pyridyl 1-pyrrolidinocarbonyl                               104  CH.sub.2 CH.sub.3                                                                          3-pyridyl 2-(methylsulfonyl)phenyl                            105  CH.sub.2 CH.sub.3                                                                          3-pyridyl 4-morpholino                                        106  CH.sub.2 CH.sub.3                                                                          3-pyridyl 2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                107  CH.sub.2 CH.sub.3                                                                          3-pyridyl 4-morpholinocarbonyl                                108  CH.sub.2 CH.sub.3                                                                          3-pyridyl 2-methyl-1-imidazolyl                               109  CH.sub.2 CH.sub.3                                                                          3-pyridyl 5-methyl-1-imidazolyl                               110  CH.sub.2 CH.sub.3                                                                          3-pyridyl 2-methylsulfonyl-1-imidazolyl                       111  CH.sub.2 CH.sub.3                                                                          2-pyrimidyl                                                                              2-(aminosulfonyl)phenyl                             112  CH.sub.2 CH.sub.3                                                                          2-pyrimidyl                                                                              2-(methylaminosulfonyl)phenyl                       113  CH.sub.2 CH.sub.3                                                                          2-pyrimidyl                                                                              1-pyrrolidinocarbonyl                               114  CH.sub.2 CH.sub.3                                                                          2-pyrimidyl                                                                              2-(methylsulfonyl)phenyl                            115  CH.sub.2 CH.sub.3                                                                          2-pyrimidyl                                                                              4-morpholino                                        116  CH.sub.2 CH.sub.3                                                                          2-pyrimidyl                                                                              2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                117  CH.sub.2 CH.sub.3                                                                          2-pyrimidyl                                                                              4-morpholinocarbonyl                                118  CH.sub.2 CH.sub.3                                                                          2-pyrimidyl                                                                              2-methyl-1-imidazolyl                               119  CH.sub.2 CH.sub.3                                                                          2-pyrimidyl                                                                              5-methyl-1-imidazolyl                               120  CH.sub.2 CH.sub.3                                                                          2-pyrimidyl                                                                              2-methylsulfonyl-1-imidazolyl                       121  CH.sub.2 CH.sub.3                                                                          5-pyrimidyl                                                                              2-(aminosulfonyl)phenyl                             122  CH.sub.2 CH.sub.3                                                                          5-pyrimidyl                                                                              2-(methylaminosulfonyl)phenyl                       123  CH.sub.2 CH.sub.3                                                                          5-pyrimidyl                                                                              1-pyrrolidinocarbonyl                               124  CH.sub.2 CH.sub.3                                                                          5-pyrimidyl                                                                              2-(methylsulfonyl)phenyl                            125  CH.sub.2 CH.sub.3                                                                          5-pyrimidyl                                                                              4-morpholino                                        126  CH.sub.2 CH.sub.3                                                                          5-pyrimidyl                                                                              2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                127  CH.sub.2 CH.sub.3                                                                          5-pyrimidyl                                                                              4-morpholinocarbonyl                                128  CH.sub.2 CH.sub.3                                                                          5-pyrimidyl                                                                              2-methyl-1-imidazolyl                               129  CH.sub.2 CH.sub.3                                                                          5-pyrimidyl                                                                              5-methyl-1-imidazolyl                               130  CH.sub.2 CH.sub.3                                                                          5-pyrimidyl                                                                              2-methylsulfonyl-1-imidazolyl                       131  CH.sub.2 CH.sub.3                                                                          2-Cl-phenyl                                                                              2-(aminosulfonyl)phenyl                             132  CH.sub.2 CH.sub.3                                                                          2-Cl-phenyl                                                                              2-(methylaminosulfonyl)phenyl                       133  CH.sub.2 CH.sub.3                                                                          2-Cl-phenyl                                                                              1-pyrrolidinocarbonyl                               134  CH.sub.2 CH.sub.3                                                                          2-Cl-phenyl                                                                              2-(methylsulfonyl)phenyl                            135  CH.sub.2 CH.sub.3                                                                          2-Cl-phenyl                                                                              4-morpholino                                        136  CH.sub.2 CH.sub.3                                                                          2-Cl-phenyl                                                                              2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                137  CH.sub.2 CH.sub.3                                                                          2-Cl-phenyl                                                                              4-morpholinocarbonyl                                138  CH.sub.2 CH.sub.3                                                                          2-Cl-phenyl                                                                              2-methyl-1-imidazolyl                               139  CH.sub.2 CH.sub.3                                                                          2-Cl-phenyl                                                                              5-methyl-1-imidazolyl                               140  CH.sub.2 CH.sub.3                                                                          2-Cl-phenyl                                                                              2-methylsulfonyl-1-imidazolyl                       141  CH.sub.2 CH.sub.3                                                                          2-F-phenyl                                                                               2-(aminosulfonyl)phenyl                             142  CH.sub.2 CH.sub.3                                                                          2-F-phenyl                                                                               2-(methylaminosulfonyl)phenyl                       143  CH.sub.2 CH.sub.3                                                                          2-F-phenyl                                                                               1-pyrrolidinocarbonyl                               144  CH.sub.2 CH.sub.3                                                                          2-F-phenyl                                                                               2-(methylsulfonyl)phenyl                            145  CH.sub.2 CH.sub.3                                                                          2-F-phenyl                                                                               4-morpholino                                        146  CH.sub.2 CH.sub.3                                                                          2-F-phenyl                                                                               2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                147  CH.sub.2 CH.sub.3                                                                          2-F-phenyl                                                                               4-morpholinocarbonyl                                148  CH.sub.2 CH.sub.3                                                                          2-F-phenyl                                                                               2-methyl-1-imidazolyl                               149  CH.sub.2 CH.sub.3                                                                          2-F-phenyl                                                                               5-methyl-1-imidazolyl                               150  CH.sub.2 CH.sub.3                                                                          2-F-phenyl                                                                               2-methylsulfonyl-1-imidazolyl                       151  CH.sub.2 CH.sub.3                                                                          2,6-diF-  2-(aminosulfonyl)phenyl                                              phenyl                                                        152  CH.sub.2 CH.sub.3                                                                          2,6-diF-  2-(methylaminosulfonyl)phenyl                                        phenyl                                                        153  CH.sub.2 CH.sub.3                                                                          2,6-diF-  1-pyrrolidinocarbonyl                                                phenyl                                                        154  CH.sub.2 CH.sub.3                                                                          2,6-diF-  2-(methylsulfonyl)phenyl                                             phenyl                                                        155  CH.sub.2 CH.sub.3                                                                          2,6-diF-  4-morpholino                                                         phenyl                                                        156  CH.sub.2 CH.sub.3                                                                          2,6-diF-  2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                                 phenyl                                                        157  CH.sub.2 CH.sub.3                                                                          2,6-diF-  4-morpholinocarbonyl                                                 phenyl                                                        158  CH.sub.2 CH.sub.3                                                                          2,6-diF-  2-methyl-1-imidazolyl                                                phenyl                                                        159  CH.sub.2 CH.sub.3                                                                          2,6-diF-  5-methyl-1-imidazolyl                                                phenyl                                                        160  CH.sub.2 CH.sub.3                                                                          2,6-diF-  2-methylsulfonyl-1-imidazolyl                                        phenyl                                                        161  CF.sub.3    phenyl    2-(aminosulfonyl)phenyl                             162  CF.sub.3    phenyl    2-(methylaminosulfonyl)phenyl                       163  CF.sub.3    phenyl    1-pyrrolidinocarbonyl                               164  CF.sub.3    phenyl    2-(methylsulfonyl)phenyl                            165  CF.sub.3    phenyl    4-morpholino                                        166  CF.sub.3    phenyl    2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                167  CF.sub.3    phenyl    4-morpholinocarbonyl                                168  CF.sub.3    phenyl    2-methyl-1-imidazolyl                               169  CF.sub.3    phenyl    5-methyl-1-imidazolyl                               170  CF.sub.3    phenyl    2-methylsulfonyl-1-imidazolyl                       171  CF.sub.3    2-pyridyl 2-(aminosulfonyl)phenyl                             172  CF.sub.3    2-pyridyl 2-(methylaminosulfonyl)phenyl                       173  CF.sub.3    2-pyridyl 1-pyrrolidinocarbonyl                               174  CF.sub.3    2-pyridyl 2-(methylsulfonyl)phenyl                            175  CF.sub.3    2-pyridyl 4-morpholino                                        176  CF.sub.3    2-pyridyl 2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                177  CF.sub.3    2-pyridyl 4-morpholinocarbonyl                                178  CF.sub.3    2-pyridyl 2-methyl-1-imidazolyl                               179  CF.sub.3    2-pyridyl 5-methyl-1-imidazolyl                               180  CF.sub.3    2-pyridyl 2-methylsulfonyl-1-imidazolyl                       181  CF.sub.3    3-pyridyl 2-(aminosulfonyl)phenyl                             182  CF.sub.3    3-pyridyl 2-(methylaminosulfonyl)phenyl                       183  CF.sub.3    3-pyridyl 1-pyrrolidinocarbonyl                               184  CF.sub.3    3-pyridyl 2-(methylsulfonyl)phenyl                            185  CF.sub.3    3-pyridyl 4-morpholino                                        186  CF.sub.3    3-pyridyl 2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                187  CF.sub.3    3-pyridyl 4-morpholinocarbonyl                                188  CF.sub.3    3-pyridyl 2-methyl-1-imidazolyl                               189  CF.sub.3    3-pyridyl 5-methyl-1-imidazolyl                               190  CF.sub.3    3-pyridyl 2-methylsulfonyl-1-imidazolyl                       191  CF.sub.3    2-pyrimidyl                                                                              2-(aminosulfonyl)phenyl                             192  CF.sub.3    2-pyrimidyl                                                                              2-(methylaminosulfonyl)phenyl                       193  CF.sub.3    2-pyrimidyl                                                                              1-pyrrolidinocarbonyl                               194  CF.sub.3    2-pyrimidyl                                                                              2-(methylsulfonyl)phenyl                            195  CF.sub.3    2-pyrimidyl                                                                              4-morpholino                                        196  CF.sub.3    2-pyrimidyl                                                                              2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                197  CF.sub.3    2-pyrimidyl                                                                              4-morpholinocarbonyl                                198  CF.sub.3    2-pyrimidyl                                                                              2-methyl-1-imidazolyl                               199  CF.sub.3    2-pyrimidyl                                                                              5-methyl-1-imidazolyl                               200  CF.sub.3    2-pyrimidyl                                                                              2-methylsulfonyl-1-imidazolyl                       201  CF.sub.3    5-pyrimidyl                                                                              2-(aminosulfonyl)phenyl                             202  CF.sub.3    5-pyrimidyl                                                                              2-(methylaminosulfonyl)phenyl                       203  CF.sub.3    5-pyrimidyl                                                                              1-pyrrolidinocarbonyl                               204  CF.sub.3    5-pyrimidyl                                                                              2-(methylsulfonyl)phenyl                            205  CF.sub.3    5-pyrimidyl                                                                              4-morpholino                                        206  CF.sub.3    5-pyrimidyl                                                                              2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                207  CF.sub.3    5-pyrimidyl                                                                              4-morpholinocarbonyl                                208  CF.sub.3    5-pyrimidyl                                                                              2-methyl-1-imidazolyl                               209  CF.sub.3    5-pyrimidyl                                                                              5-methyl-1-imidazolyl                               210  CF.sub.3    5-pyrimidyl                                                                              2-methylsulfonyl-1-imidazolyl                       211  CF.sub.3    2-Cl-phenyl                                                                              2-(aminosulfonyl)phenyl                             212  CF.sub.3    2-Cl-phenyl                                                                              2-(methylaminosulfonyl)phenyl                       213  CF.sub.3    2-Cl-phenyl                                                                              1-pyrrolidinocarbonyl                               214  CF.sub.3    2-Cl-phenyl                                                                              2-(methylsulfonyl)phenyl                            215  CF.sub.3    2-Cl-phenyl                                                                              4-morpholino                                        216  CF.sub.3    2-Cl-phenyl                                                                              2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                217  CF.sub.3    2-Cl-phenyl                                                                              4-morpholinocarbonyl                                218  CF.sub.3    2-Cl-phenyl                                                                              2-methyl-1-imidazolyl                               219  CF.sub.3    2-Cl-phenyl                                                                              5-methyl-1-imidazolyl                               220  CF.sub.3    2-Cl-phenyl                                                                              2-methylsulfonyl-1-imidazolyl                       221  CF.sub.3    2-F-phenyl                                                                               2-(aminosulfonyl)phenyl                             222  CF.sub.3    2-F-phenyl                                                                               2-(methylaminosulfonyl)phenyl                       223  CF.sub.3    2-F-phenyl                                                                               1-pyrrolidinocarbonyl                               224  CF.sub.3    2-F-phenyl                                                                               2-(methylsulfonyl)phenyl                            225  CF.sub.3    2-F-phenyl                                                                               4-morpholino                                        226  CF.sub.3    2-F-phenyl                                                                               2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                227  CF.sub.3    2-F-phenyl                                                                               4-morpholinocarbonyl                                228  CF.sub.3    2-F-phenyl                                                                               2-methyl-1-imidazolyl                               229  CF.sub.3    2-F-phenyl                                                                               5-methyl-1-imidazolyl                               230  CF.sub.3    2-F-phenyl                                                                               2-methylsulfonyl-1-imidazolyl                       231  CF.sub.3    2,6-diF-  2-(aminosulfonyl)phenyl                                              phenyl                                                        232  CF.sub.3    2,6-diF-  2-(methylaminosulfonyl)phenyl                                        phenyl                                                        233  CF.sub.3    2,6-diF-  1-pyrrolidinocarbonyl                                                phenyl                                                        234  CF.sub.3    2,6-diF-  2-(methylsulfonyl)phenyl                                             phenyl                                                        235  CF.sub.3    2,6-diF-  4-morpholino                                                         phenyl                                                        236  CF.sub.3    2,6-diF-  2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                                 phenyl                                                        237  CF.sub.3    2,6-diF-  4-morpholinocarbonyl                                                 phenyl                                                        238  CF.sub.3    2,6-diF-  2-methyl-1-imidazolyl                                                phenyl                                                        239  CF.sub.3    2,6-diF-  5-methyl-1-imidazolyl                                                phenyl                                                        240  CF.sub.3    2,6-diF-  2-methylsulfonyl-1-imidazolyl                                        phenyl                                                        241  SCH.sub.3   phenyl    2-(aminosulfonyl)phenyl                             242  SCH.sub.3   phenyl    2-(methylaminosulfonyl)phenyl                       243  SCH.sub.3   phenyl    1-pyrrolidinocarbonyl                               244  SCH.sub.3   phenyl    2-(methylsulfonyl)phenyl                            245  SCH.sub.3   phenyl    4-morpholino                                        246  SCH.sub.3   phenyl    2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                247  SCH.sub.3   phenyl    4-morpholinocarbonyl                                248  SCH.sub.3   phenyl    2-methyl-1-imidazolyl                               249  SCH.sub.3   phenyl    5-methyl-1-imidazolyl                               250  SCH.sub.3   phenyl    2-methylsulfonyl-1-imidazolyl                       251  SCH.sub.3   2-pyridyl 2-(aminosulfonyl)phenyl                             252  SCH.sub.3   2-pyridyl 2-(methylaminosulfonyl)phenyl                       253  SCH.sub.3   2-pyridyl 1-pyrrolidinocarbonyl                               254  SCH.sub.3   2-pyridyl 2-(methylsulfonyl)phenyl                            255  SCH.sub.3   2-pyridyl 4-morpholino                                        256  SCH.sub.3   2-pyridyl 2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                257  SCH.sub.3   2-pyridyl 4-morpholinocarbonyl                                258  SCH.sub.3   2-pyridyl 2-methyl-1-imidazolyl                               259  SCH.sub.3   2-pyridyl 5-methyl-1-imidazolyl                               260  SCH.sub.3   2-pyridyl 2-methylsulfonyl-1-imidazolyl                       261  SCH.sub.3   3-pyridyl 2-(aminosulfonyl)phenyl                             262  SCH.sub.3   3-pyridyl 2-(methylaminosulfonyl)phenyl                       263  SCH.sub.3   3-pyridyl 1-pyrrolidinocarbonyl                               264  SCH.sub.3   3-pyridyl 2-(methylsulfonyl)phenyl                            265  SCH.sub.3   3-pyridyl 4-morpholino                                        266  SCH.sub.3   3-pyridyl 2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                267  SCH.sub.3   3-pyridyl 4-morpholinocarbonyl                                268  SCH.sub.3   3-pyridyl 2-methyl-1-imidazolyl                               269  SCH.sub.3   3-pyridyl 5-methyl-1-imidazolyl                               270  SCH.sub.3   3-pyridyl 2-methylsulfonyl-1-imidazolyl                       271  SCH.sub.3   2-pyrimidyl                                                                              2-(aminosulfonyl)phenyl                             272  SCH.sub.3   2-pyrimidyl                                                                              2-(methylaminosulfonyl)phenyl                       273  SCH.sub.3   2-pyrimidyl                                                                              1-pyrrolidinocarbonyl                               274  SCH.sub.3   2-pyrimidyl                                                                              2-(methylsulfonyl)phenyl                            275  SCH.sub.3   2-pyrimidyl                                                                              4-morpholino                                        276  SCH.sub.3   2-pyrimidyl                                                                              2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                277  SCH.sub.3   2-pyrimidyl                                                                              4-morpholinocarbonyl                                278  SCH.sub.3   2-pyrimidyl                                                                              2-methyl-1-imidazolyl                               279  SCH.sub.3   2-pyrimidyl                                                                              5-methyl-1-imidazolyl                               280  SCH.sub.3   2-pyrimidyl                                                                              2-methylsulfonyl-1-imidazolyl                       281  SCH.sub.3   5-pyrimidyl                                                                              2-(aminosulfonyl)phenyl                             282  SCH.sub.3   5-pyrimidyl                                                                              2-(methylaminosulfonyl)phenyl                       283  SCH.sub.3   5-pyrimidyl                                                                              1-pyrrolidinocarbonyl                               284  SCH.sub.3   5-pyrimidyl                                                                              2-(methylsulfonyl)phenyl                            285  SCH.sub.3   5-pyrimidyl                                                                              4-morpholino                                        286  SCH.sub.3   5-pyrimidyl                                                                              2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                287  SCH.sub.3   5-pyrimidyl                                                                              4-morpholinocarbonyl                                288  SCH.sub.3   5-pyrimidyl                                                                              2-methyl-1-imidazolyl                               289  SCH.sub.3   5-pyrimidyl                                                                              5-methyl-1-imidazolyl                               290  SCH.sub.3   5-pyrimidyl                                                                              2-methylsulfonyl-1-imidazolyl                       291  SCH.sub.3   2-Cl-phenyl                                                                              2-(aminosulfonyl)phenyl                             292  SCH.sub.3   2-Cl-phenyl                                                                              2-(methylaminosulfonyl)phenyl                       293  SCH.sub.3   2-Cl-phenyl                                                                              1-pyrrolidinocarbonyl                               294  SCH.sub.3   2-Cl-phenyl                                                                              2-(methylsulfonyl)phenyl                            295  SCH.sub.3   2-Cl-phenyl                                                                              4-morpholino                                        296  SCH.sub.3   2-Cl-phenyl                                                                              2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                297  SCH.sub.3   2-Cl-phenyl                                                                              4-morpholinocarbonyl                                298  SCH.sub.3   2-Cl-phenyl                                                                              2-methyl-1-imidazolyl                               299  SCH.sub.3   2-Cl-phenyl                                                                              5-methyl-1-imidazolyl                               300  SCH.sub.3   2-Cl-phenyl                                                                              2-methylsulfonyl-1-imidazolyl                       301  SCH.sub.3   2-F-phenyl                                                                               2-(aminosulfonyl)phenyl                             302  SCH.sub.3   2-F-phenyl                                                                               2-(methylaminosulfonyl)phenyl                       303  SCH.sub.3   2-F-phenyl                                                                               1-pyrrolidinocarbonyl                               304  SCH.sub.3   2-F-phenyl                                                                               2-(methylsulfonyl)phenyl                            305  SCH.sub.3   2-F-phenyl                                                                               4-morpholino                                        306  SCH.sub.3   2-F-phenyl                                                                               2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                307  SCH.sub.3   2-F-phenyl                                                                               4-morpholinocarbonyl                                308  SCH.sub.3   2-F-phenyl                                                                               2-methyl-1-imidazolyl                               309  SCH.sub.3   2-F-phenyl                                                                               5-methyl-1-imidazolyl                               310  SCH.sub.3   2-F-phenyl                                                                               2-methylsulfonyl-1-imidazolyl                       311  SCH.sub.3   2,6-diF-  2-(aminosulfonyl)phenyl                                              phenyl                                                        312  SCH.sub.3   2,6-diF-  2-(methylaminosulfonyl)phenyl                                        phenyl                                                        313  SCH.sub.3   2,6-diF-  1-pyrrolidinocarbonyl                                                phenyl                                                        314  SCH.sub.3   2,6-diF-  2-(methylsulfonyl)phenyl                                             phenyl                                                        315  SCH.sub.3   2,6-diF-  4-morpholino                                                         phenyl                                                        316  SCH.sub.3   2,6-diF-  2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                                 phenyl                                                        317  SCH.sub.3   2,6-diF-  4-morpholinocarbonyl                                                 phenyl                                                        318  SCH.sub.3   2,6-diF-  2-methyl-1-imidazolyl                                                phenyl                                                        319  SCH.sub.3   2,6-diF-  5-methyl-1-imidazolyl                                                phenyl                                                        320  SCH.sub.3   2,6-diF-  2-methylsulfonyl-1-imidazolyl                                        phenyl                                                        321  SOCH.sub.3  phenyl    2-(aminosulfonyl)phenyl                             322  SOCH.sub.3  phenyl    2-(methylaminosulfonyl)phenyl                       323  SOCH.sub.3  phenyl    1-pyrrolidinocarbonyl                               324  SOCH.sub.3  phenyl    2-(methylsulfonyl)phenyl                            325  SOCH.sub.3  phenyl    4-morpholino                                        326  SOCH.sub.3  phenyl    2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                327  SOCH.sub.3  phenyl    4-morpholinocarbonyl                                328  SOCH.sub.3  phenyl    2-methyl-1-imidazolyl                               329  SOCH.sub.3  phenyl    5-methyl-1-imidazolyl                               330  SOCH.sub.3  phenyl    2-methylsulfonyl-1-imidazolyl                       331  SOCH.sub.3  2-pyridyl 2-(aminosulfonyl)phenyl                             332  SOCH.sub.3  2-pyridyl 2-(methylaminosulfonyl)phenyl                       333  SOCH.sub.3  2-pyridyl 1-pyrrolidinocarbonyl                               334  SOCH.sub.3  2-pyridyl 2-(methylsulfonyl)phenyl                            335  SOCH.sub.3  2-pyridyl 4-morpholino                                        336  SOCH.sub.3  2-pyridyl 2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                337  SOCH.sub.3  2-pyridyl 4-morpholinocarbonyl                                338  SOCH.sub.3  2-pyridyl 2-methyl-1-imidazolyl                               339  SOCH.sub.3  2-pyridyl 5-methyl-1-imidazolyl                               340  SOCH.sub.3  2-pyridyl 2-methylsulfonyl-1-imidazolyl                       341  SOCH.sub.3  3-pyridyl 2-(aminosulfonyl)phenyl                             342  SOCH.sub.3  3-pyridyl 2-(methylaminosulfonyl)phenyl                       343  SOCH.sub.3  3-pyridyl 1-pyrrolidinocarbonyl                               344  SOCH.sub.3  3-pyridyl 2-(methylsulfonyl)phenyl                            345  SOCH.sub.3  3-pyridyl 4-morpholino                                        346  SOCH.sub.3  3-pyridyl 2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                347  SOCH.sub.3  3-pyridyl 4-morpholinocarbonyl                                348  SOCH.sub.3  3-pyridyl 2-methyl-1-imidazolyl                               349  SOCH.sub.3  3-pyridyl 5-methyl-1-imidazolyl                               350  SOCH.sub.3  3-pyridyl 2-methylsulfonyl-1-imidazolyl                       351  SOCH.sub.3  2-pyrimidyl                                                                              2-(aminosulfonyl)phenyl                             352  SOCH.sub.3  2-pyrimidyl                                                                              2-(methylaminosulfonyl)phenyl                       353  SOCH.sub.3  2-pyrimidyl                                                                              1-pyrrolidinocarbonyl                               354  SOCH.sub.3  2-pyrimidyl                                                                              2-(methylsulfonyl)phenyl                            355  SOCH.sub.3  2-pyrimidyl                                                                              4-morpholino                                        356  SOCH.sub.3  2-pyrimidyl                                                                              2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                357  SOCH.sub.3  2-pyrimidyl                                                                              4-morpholinocarbonyl                                358  SOCH.sub.3  2-pyrimidyl                                                                              2-methyl-1-imidazolyl                               359  SOCH.sub.3  2-pyrimidyl                                                                              5-methyl-1-imidazolyl                               360  SOCH.sub.3  2-pyrimidyl                                                                              2-methylsulfonyl-1-imidazolyl                       361  SOCH.sub.3  5-pyrimidyl                                                                              2-(aminosulfonyl)phenyl                             362  SOCH.sub.3  5-pyrimidyl                                                                              2-(methylaminosulfonyl)phenyl                       363  SOCH.sub.3  5-pyrimidyl                                                                              1-pyrrolidinocarbonyl                               364  SOCH.sub.3  5-pyrimidyl                                                                              2-(methylsulfonyl)phenyl                            365  SOCH.sub.3  5-pyrimidyl                                                                              4-morpholino                                        366  SOCH.sub.3  5-pyrimidyl                                                                              2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                367  SOCH.sub.3  5-pyrimidyl                                                                              4-morpholinocarbonyl                                368  SOCH.sub.3  5-pyrimidyl                                                                              2-methyl-1-imidazolyl                               369  SOCH.sub.3  5-pyrimidyl                                                                              5-methyl-1-imidazolyl                               370  SOCH.sub.3  5-pyrimidyl                                                                              2-methylsulfonyl-1-imidazolyl                       371  SOCH.sub.3  2-Cl-phenyl                                                                              2-(aminosulfonyl)phenyl                             372  SOCH.sub.3  2-Cl-phenyl                                                                              2-(methylaminosulfonyl)phenyl                       373  SOCH.sub.3  2-Cl-phenyl                                                                              1-pyrrolidinocarbonyl                               374  SOCH.sub.3  2-Cl-phenyl                                                                              2-(methylsulfonyl)phenyl                            375  SOCH.sub.3  2-Cl-phenyl                                                                              4-morpholino                                        376  SOCH.sub.3  2-Cl-phenyl                                                                              2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                377  SOCH.sub.3  2-Cl-phenyl                                                                              4-morpholinocarbonyl                                378  SOCH.sub.3  2-Cl-phenyl                                                                              2-methyl-1-imidazolyl                               379  SOCH.sub.3  2-Cl-phenyl                                                                              5-methyl-1-imidazolyl                               380  SOCH.sub.3  2-Cl-phenyl                                                                              2-methylsulfonyl-1-imidazolyl                       381  SOCH.sub.3  2-F-phenyl                                                                               2-(aminosulfonyl)phenyl                             382  SOCH.sub.3  2-F-phenyl                                                                               2-(methylaminosulfonyl)phenyl                       383  SOCH.sub.3  2-F-phenyl                                                                               1-pyrrolidinocarbonyl                               384  SOCH.sub.3  2-F-phenyl                                                                               2-(methylsulfonyl)phenyl                            385  SOCH.sub.3  2-F-phenyl                                                                               4-morpholino                                        386  SOCH.sub.3  2-F-phenyl                                                                               2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                387  SOCH.sub.3  2-F-phenyl                                                                               4-morpholinocarbonyl                                388  SOCH.sub.3  2-F-phenyl                                                                               2-methyl-1-imidazolyl                               389  SOCH.sub.3  2-F-phenyl                                                                               5-methyl-1-imidazolyl                               390  SOCH.sub.3  2-F-phenyl                                                                               2-methylsulfonyl-1-imidazolyl                       391  SOCH.sub.3  2,6-diF-  2-(aminosulfonyl)phenyl                                              phenyl                                                        392  SOCH.sub.3  2,6-diF-  2-(methylaminosulfonyl)phenyl                                        phenyl                                                        393  SOCH.sub.3  2,6-diF-  1-pyrrolidinocarbonyl                                                phenyl                                                        394  SOCH.sub.3  2,6-diF-  2-(methylsulfonyl)phenyl                                             phenyl                                                        395  SOCH.sub.3  2,6-diF-  4-morpholino                                                         phenyl                                                        396  SOCH.sub.3  2,6-diF-  2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                                 phenyl                                                        397  SOCH.sub.3  2,6-diF-  4-morpholinocarbonyl                                                 phenyl                                                        398  SOCH.sub.3  2,6-diF-  2-methyl-1-imidazolyl                                                phenyl                                                        399  SOCH.sub.3  2,6-diF-  5-methyl-1-imidazolyl                                                phenyl                                                        400  SOCH.sub.3  2,6-diF-  2-methylsulfonyl-1-imidazolyl                                        phenyl                                                        401  SO.sub.2 CH.sub.3                                                                          phenyl    2-(aminosulfonyl)phenyl                             402  SO.sub.2 CH.sub.3                                                                          phenyl    2-(methylaminosulfonyl)phenyl                       403  SO.sub.2 CH.sub.3                                                                          phenyl    1-pyrrolidinocarbonyl                               404  SO.sub.2 CH.sub.3                                                                          phenyl    2-(methylsulfonyl)phenyl                            405  SO.sub.2 CH.sub.3                                                                          phenyl    4-morpholino                                        406  SO.sub.2 CH.sub.3                                                                          phenyl    2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                407  SO.sub.2 CH.sub.3                                                                          phenyl    4-morpholinocarbonyl                                408  SO.sub.2 CH.sub.3                                                                          phenyl    2-methyl-1-imidazolyl                               409  SO.sub.2 CH.sub.3                                                                          phenyl    5-methyl-1-imidazolyl                               410  SO.sub.2 CH.sub.3                                                                          phenyl    2-methylsulfonyl-1-imidazolyl                       411  SO.sub.2 CH.sub.3                                                                          2-pyridyl 2-(aminosulfonyl)phenyl                             412  SO.sub.2 CH.sub.3                                                                          2-pyridyl 2-(methylaminosulfonyl)phenyl                       413  SO.sub.2 CH.sub.3                                                                          2-pyridyl 1-pyrrolidinocarbonyl                               414  SO.sub.2 CH.sub.3                                                                          2-pyridyl 2-(methylsulfonyl)phenyl                            415  SO.sub.2 CH.sub.3                                                                          2-pyridyl 4-morpholino                                        416  SO.sub.2 CH.sub.3                                                                          2-pyridyl 2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                417  SO.sub.2 CH.sub.3                                                                          2-pyridyl 4-morpholinocarbonyl                                418  SO.sub.2 CH.sub.3                                                                          2-pyridyl 2-methyl-1-imidazolyl                               419  SO.sub.2 CH.sub.3                                                                          2-pyridyl 5-methyl-1-imidazolyl                               420  SO.sub.2 CH.sub.3                                                                          2-pyridyl 2-methylsulfonyl-1-imidazolyl                       421  SO.sub.2 CH.sub.3                                                                          3-pyridyl 2-(aminosulfonyl)phenyl                             422  SO.sub.2 CH.sub.3                                                                          3-pyridyl 2-(methylaminosulfonyl)phenyl                       423  SO.sub.2 CH.sub.3                                                                          3-pyridyl 1-pyrrolidinocarbonyl                               424  SO.sub.2 CH.sub.3                                                                          3-pyridyl 2-(methylsulfonyl)phenyl                            425  SO.sub.2 CH.sub.3                                                                          3-pyridyl 4-morpholino                                        426  SO.sub.2 CH.sub.3                                                                          3-pyridyl 2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                427  SO.sub.2 CH.sub.3                                                                          3-pyridyl 4-morpholinocarbonyl                                428  SO.sub.2 CH.sub.3                                                                          3-pyridyl 2-methyl-1-imidazolyl                               429  SO.sub.2 CH.sub.3                                                                          3-pyridyl 5-methyl-1-imidazolyl                               430  SO.sub.2 CH.sub.3                                                                          3-pyridyl 2-methylsulfonyl-1-imidazolyl                       431  SO.sub.2 CH.sub.3                                                                          2-pyrimidyl                                                                              2-(aminosulfonyl)phenyl                             432  SO.sub.2 CH.sub.3                                                                          2-pyrimidyl                                                                              2-(methylaminosulfonyl)phenyl                       433  SO.sub.2 CH.sub.3                                                                          2-pyrimidyl                                                                              1-pyrrolidinocarbonyl                               434  SO.sub.2 CH.sub.3                                                                          2-pyrimidyl                                                                              2-(methylsulfonyl)phenyl                            435  SO.sub.2 CH.sub.3                                                                          2-pyrimidyl                                                                              4-morpholino                                        436  SO.sub.2 CH.sub.3                                                                          2-pyrimidyl                                                                              2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                437  SO.sub.2 CH.sub.3                                                                          2-pyrimidyl                                                                              4-morpholinocarbonyl                                438  SO.sub.2 CH.sub.3                                                                          2-pyrimidyl                                                                              2-methyl-1-imidazolyl                               439  SO.sub.2 CH.sub.3                                                                          2-pyrimidyl                                                                              5-methyl-1-imidazolyl                               440  SO.sub.2 CH.sub.3                                                                          2-pyrimidyl                                                                              2-methylsulfonyl-1-imidazolyl                       441  SO.sub.2 CH.sub.3                                                                          5-pyrimidyl                                                                              2-(aminosulfonyl)phenyl                             442  SO.sub.2 CH.sub.3                                                                          5-pyrimidyl                                                                              2-(methylaminosulfonyl)phenyl                       443  SO.sub.2 CH.sub.3                                                                          5-pyrimidyl                                                                              1-pyrrolidinocarbonyl                               444  SO.sub.2 CH.sub.3                                                                          5-pyrimidyl                                                                              2-(methylsulfonyl)phenyl                            445  SO.sub.2 CH.sub.3                                                                          5-pyrimidyl                                                                              4-morpholino                                        446  SO.sub.2 CH.sub.3                                                                          5-pyrimidyl                                                                              2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                447  SO.sub.2 CH.sub.3                                                                          5-pyrimidyl                                                                              4-morpholinocarbonyl                                448  SO.sub.2 CH.sub.3                                                                          5-pyrimidyl                                                                              2-methyl-1-imidazolyl                               449  SO.sub.2 CH.sub.3                                                                          5-pyrimidyl                                                                              5-methyl-1-imidazolyl                               450  SO.sub.2 CH.sub.3                                                                          5-pyrimidyl                                                                              2-methylsulfonyl-1-imidazolyl                       451  SO.sub.2 CH.sub.3                                                                          2-Cl-phenyl                                                                              2-(aminosulfonyl)phenyl                             452  SO.sub.2 CH.sub.3                                                                          2-Cl-phenyl                                                                              2-(methylaminosulfonyl)phenyl                       453  SO.sub.2 CH.sub.3                                                                          2-Cl-phenyl                                                                              1-pyrrolidinocarbonyl                               454  SO.sub.2 CH.sub.3                                                                          2-Cl-phenyl                                                                              2-(methylsulfonyl)phenyl                            455  SO.sub.2 CH.sub.3                                                                          2-Cl-phenyl                                                                              4-morpholino                                        456  SO.sub.2 CH.sub.3                                                                          2-Cl-phenyl                                                                              2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                457  SO.sub.2 CH.sub.3                                                                          2-Cl-phenyl                                                                              4-morpholinocarbonyl                                458  SO.sub.2 CH.sub.3                                                                          2-Cl-phenyl                                                                              2-methyl-1-imidazolyl                               459  SO.sub.2 CH.sub.3                                                                          2-Cl-phenyl                                                                              5-methyl-1-imidazolyl                               460  SO.sub.2 CH.sub.3                                                                          2-Cl-phenyl                                                                              2-methylsulfonyl-1-imidazolyl                       461  SO.sub.2 CH.sub.3                                                                          2-F-phenyl                                                                               2-(aminosulfonyl)phenyl                             462  SO.sub.2 CH.sub.3                                                                          2-F-phenyl                                                                               2-(methylaminosulfonyl)phenyl                       463  SO.sub.2 CH.sub.3                                                                          2-F-phenyl                                                                               1-pyrrolidinocarbonyl                               464  SO.sub.2 CH.sub.3                                                                          2-F-phenyl                                                                               2-(methylsulfonyl)phenyl                            465  SO.sub.2 CH.sub.3                                                                          2-F-phenyl                                                                               4-morpholino                                        466  SO.sub.2 CH.sub.3                                                                          2-F-phenyl                                                                               2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                467  SO.sub.2 CH.sub.3                                                                          2-F-phenyl                                                                               4-morpholinocarbonyl                                468  SO.sub.2 CH.sub.3                                                                          2-F-phenyl                                                                               2-methyl-1-imidazolyl                               469  SO.sub.2 CH.sub.3                                                                          2-F-phenyl                                                                               5-methyl-1-imidazolyl                               470  SO.sub.2 CH.sub.3                                                                          2-F-phenyl                                                                               2-methylsulfonyl-1-imidazolyl                       471  SO.sub.2 CH.sub.3                                                                          2,6-diF-  2-(aminosulfonyl)phenyl                                              phenyl                                                        472  SO.sub.2 CH.sub.3                                                                          2,6-diF-  2-(methylaminosulfonyl)phenyl                                        phenyl                                                        473  SO.sub.2 CH.sub.3                                                                          2,6-diF-  1-pyrrolidinocarbonyl                                                phenyl                                                        474  SO.sub.2 CH.sub.3                                                                          2,6-diF-  2-(methylsulfonyl)phenyl                                             phenyl                                                        475  SO.sub.2 CH.sub.3                                                                          2,6-diF-  4-morpholino                                                         phenyl                                                        476  SO.sub.2 CH.sub.3                                                                          2,6-diF-  2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                                 phenyl                                                        477  SO.sub.2 CH.sub.3                                                                          2,6-diF-  4-morpholinocarbonyl                                                 phenyl                                                        478  SO.sub.2 CH.sub.3                                                                          2,6-diF-  2-methyl-1-imidazolyl                                                phenyl                                                        479  SO.sub.2 CH.sub.3                                                                          2,6-diF-  5-methyl-1-imidazolyl                                                phenyl                                                        480  SO.sub.2 CH.sub.3                                                                          2,6-diF-  2-methylsulfonyl-1-imidazolyl                                        phenyl                                                        481  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             phenyl    2-(aminosulfonyl)phenyl                             482  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             phenyl    2-(methylaminosulfonyl)phenyl                       483  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             phenyl    1-pyrrolidinocarbonyl                               484  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             phenyl    2-(methylsulfonyl)phenyl                            485  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             phenyl    4-morpholino                                        486  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             phenyl    2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                487  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             phenyl    4-morpholinocarbonyl                                488  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             phenyl    2-methyl-1-imidazolyl                               489  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             phenyl    5-methyl-1-imidazolyl                               490  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             phenyl    2-methylsulfonyl-1-imidazolyl                       491  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2-pyridyl 2-(aminosulfonyl)phenyl                             492  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2-pyridyl 2-(methylaminosulfonyl)phenyl                       493  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2-pyridyl 1-pyrrolidinocarbonyl                               494  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2-pyridyl 2-(methylsulfonyl)phenyl                            495  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2-pyridyl 4-morpholino                                        496  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2-pyridyl 2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                497  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2-pyridyl 4-morpholinocarbonyl                                498  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2-pyridyl 2-methyl-1-imidazolyl                               499  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2-pyridyl 5-methyl-1-imidazolyl                               500  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2-pyridyl 2-methylsulfonyl-1-imidazolyl                       501  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             3-pyridyl 2-(aminosulfonyl)phenyl                             502  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             3-pyridyl 2-(methylaminosulfonyl)phenyl                       503  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             3-pyridyl 1-pyrrolidinocarbonyl                               504  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             3-pyridyl 2-(methylsulfonyl)phenyl                            505  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             3-pyridyl 4-morpholino                                        506  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             3-pyridyl 2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                507  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             3-pyridyl 4-morpholinocarbonyl                                508  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             3-pyridyl 2-methyl-1-imidazolyl                               509  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             3-pyridyl 5-methyl-1-imidazolyl                               510  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             3-pyridyl 2-methylsulfonyl-1-imidazolyl                       511  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2-pyrimidyl                                                                              2-(aminosulfonyl)phenyl                             512  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2-pyrimidyl                                                                              2-(methylaminosulfonyl)phenyl                       513  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2-pyrimidyl                                                                              1-pyrrolidinocarbonyl                               514  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2-pyrimidyl                                                                              2-(methylsulfonyl)phenyl                            515  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2-pyrimidyl                                                                              4-morpholino                                        516  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2-pyrimidyl                                                                              2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                517  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2-pyrimidyl                                                                              4-morpholinocarbonyl                                518  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2-pyrimidyl                                                                              2-methyl-1-imidazolyl                               519  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2-pyrimidyl                                                                              5-methyl-1-imidazolyl                               520  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2-pyrimidyl                                                                              2-methylsulfonyl-1-imidazolyl                       521  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             5-pyrimidyl                                                                              2-(aminosulfonyl)phenyl                             522  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             5-pyrimidyl                                                                              2-(methylaminosulfonyl)phenyl                       523  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             5-pyrimidyl                                                                              1-pyrrolidinocarbonyl                               524  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             5-pyrimidyl                                                                              2-(methylsulfonyl)phenyl                            525  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             5-pyrimidyl                                                                              4-morpholino                                        526  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             5-pyrimidyl                                                                              2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                527  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             5-pyrimidyl                                                                              4-morpholinocarbonyl                                528  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             5-pyrimidyl                                                                              2-methyl-1-imidazolyl                               529  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             5-pyrimidyl                                                                              5-methyl-1-imidazolyl                               530  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             5-pyrimidyl                                                                              2-methylsulfonyl-1-imidazolyl                       531  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2-Cl-phenyl                                                                              2-(aminosulfonyl)phenyl                             532  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2-Cl-phenyl                                                                              2-(methylaminosulfonyl)phenyl                       533  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2-Cl-phenyl                                                                              1-pyrrolidinocarbonyl                               534  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2-Cl-phenyl                                                                              2-(methylsulfonyl)phenyl                            535  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2-Cl-phenyl                                                                              4-morpholino                                        536  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2-Cl-phenyl                                                                              2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                537  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2-Cl-phenyl                                                                              4-morpholinocarbonyl                                538  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2-Cl-phenyl                                                                              2-methyl-1-imidazolyl                               539  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2-Cl-phenyl                                                                              5-methyl-1-imidazolyl                               540  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2-Cl-phenyl                                                                              2-methylsulfonyl-1-imidazolyl                       541  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2-F-phenyl                                                                               2-(aminosulfonyl)phenyl                             542  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2-F-phenyl                                                                               2-(methylaminosulfonyl)phenyl                       543  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2-F-phenyl                                                                               1-pyrrolidinocarbonyl                               544  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2-F-phenyl                                                                               2-(methylsulfonyl)phenyl                            545  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2-F-phenyl                                                                               4-morpholino                                        546  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2-F-phenyl                                                                               2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                547  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2-F-phenyl                                                                               4-morpholinocarbonyl                                548  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2-F-phenyl                                                                               2-methyl-1-imidazolyl                               549  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2-F-phenyl                                                                               5-methyl-1-imidazolyl                               550  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2-F-phenyl                                                                               2-methylsulfonyl-1-imidazolyl                       551  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2,6-diF-  2-(aminosulfonyl)phenyl                                              phenyl                                                        552  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2,6-diF-  2-(methylaminosulfonyl)phenyl                                        phenyl                                                        553  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2,6-diF-  1-pyrrolidinocarbonyl                                                phenyl                                                        554  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2,6-diF-  2-(methylsulfonyl)phenyl                                             phenyl                                                        555  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2,6-diF-  4-morpholino                                                         phenyl                                                        556  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2,6-diF-  2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                                 phenyl                                                        557  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2,6-diF-  4-morpholinocarbonyl                                                 phenyl                                                        558  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2,6-diF-  2-methyl-1-imidazolyl                                                phenyl                                                        559  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2,6-diF-  5-methyl-1-imidazolyl                                                phenyl                                                        560  CH.sub.2 NH--SO.sub.2 CH.sub.3                                                             2,6-diF-  2-methylsulfonyl-1-imidazolyl                                        phenyl                                                        561  Cl          phenyl    2-(aminosulfonyl)phenyl                             562  Cl          phenyl    2-(methylaminosulfonyl)phenyl                       563  Cl          phenyl    1-pyrrolidinocarbonyl                               564  Cl          phenyl    2-(methylsulfonyl)phenyl                            565  Cl          phenyl    4-morpholino                                        566  Cl          phenyl    2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                567  Cl          phenyl    4-morpholinocarbonyl                                568  Cl          phenyl    2-methyl-1-imidazolyl                               569  Cl          phenyl    5-methyl-1-imidazolyl                               570  Cl          phenyl    2-methylsulfonyl-1-imidazolyl                       571  Cl          2-pyridyl 2-(aminosulfonyl)phenyl                             572  Cl          2-pyridyl 2-(methylaminosulfonyl)phenyl                       573  Cl          2-pyridyl 1-pyrrolidinocarbonyl                               574  Cl          2-pyridyl 2-(methylsulfonyl)phenyl                            575  Cl          2-pyridyl 4-morpholino                                        576  Cl          2-pyridyl 2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                577  Cl          2-pyridyl 4-morpholinocarbonyl                                578  Cl          2-pyridyl 2-methyl-1-imidazolyl                               579  Cl          2-pyridyl 5-methyl-1-imidazolyl                               580  Cl          2-pyridyl 2-methylsulfonyl-1-imidazolyl                       581  Cl          3-pyridyl 2-(aminosulfonyl)phenyl                             582  Cl          3-pyridyl 2-(methylaminosulfonyl)phenyl                       583  Cl          3-pyridyl 1-pyrrolidinocarbonyl                               584  Cl          3-pyridyl 2-(methylsulfonyl)phenyl                            585  Cl          3-pyridyl 4-morpholino                                        586  Cl          3-pyridyl 2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                587  Cl          3-pyridyl 4-morpholinocarbonyl                                588  Cl          3-pyridyl 2-methyl-1-imidazolyl                               589  Cl          3-pyridyl 5-methyl-1-imidazolyl                               590  Cl          3-pyridyl 2-methylsulfonyl-1-imidazolyl                       591  Cl          2-pyrimidyl                                                                              2-(aminosulfonyl)phenyl                             592  Cl          2-pyrimidyl                                                                              2-(methylaminosulfonyl)phenyl                       593  Cl          2-pyrimidyl                                                                              1-pyrrolidinocarbonyl                               594  Cl          2-pyrimidyl                                                                              2-(methylsulfonyl)phenyl                            595  Cl          2-pyrimidyl                                                                              4-morpholino                                        596  Cl          2-pyrimidyl                                                                              2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                597  Cl          2-pyrimidyl                                                                              4-morpholinocarbonyl                                598  Cl          2-pyrimidyl                                                                              2-methyl-1-imidazolyl                               599  Cl          2-pyrimidyl                                                                              5-methyl-1-imidazolyl                               600  Cl          2-pyrimidyl                                                                              2-methylsulfonyl-1-imidazolyl                       601  Cl          5-pyrimidyl                                                                              2-(aminosulfonyl)phenyl                             602  Cl          5-pyrimidyl                                                                              2-(methylaminosulfonyl)phenyl                       603  Cl          5-pyrimidyl                                                                              1-pyrrolidinocarbonyl                               604  Cl          5-pyrimidyl                                                                              2-(methylsulfonyl)phenyl                            605  Cl          5-pyrimidyl                                                                              4-morpholino                                        606  Cl          5-pyrimidyl                                                                              2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                607  Cl          5-pyrimidyl                                                                              4-morpholinocarbonyl                                608  Cl          5-pyrimidyl                                                                              2-methyl-1-imidazolyl                               609  Cl          5-pyrimidyl                                                                              5-methyl-1-imidazolyl                               610  Cl          5-pyrimidyl                                                                              2-methylsulfonyl-1-imidazolyl                       611  Cl          2-Cl-phenyl                                                                              2-(aminosulfonyl)phenyl                             612  Cl          2-Cl-phenyl                                                                              2-(methylaminosulfonyl)phenyl                       613  Cl          2-Cl-phenyl                                                                              1-pyrrolidinocarbonyl                               614  Cl          2-Cl-phenyl                                                                              2-(methylsulfonyl)phenyl                            615  Cl          2-Cl-phenyl                                                                              4-morpholino                                        616  Cl          2-Cl-phenyl                                                                              2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                617  Cl          2-Cl-phenyl                                                                              4-morpholinocarbonyl                                618  Cl          2-Cl-phenyl                                                                              2-methyl-1-imidazolyl                               619  Cl          2-Cl-phenyl                                                                              5-methyl-1-imidazolyl                               620  Cl          2-Cl-phenyl                                                                              2-methylsulfonyl-1-imidazolyl                       621  Cl          2-F-phenyl                                                                               2-(aminosulfonyl)phenyl                             622  Cl          2-F-phenyl                                                                               2-(methylaminosulfonyl)phenyl                       623  Cl          2-F-phenyl                                                                               1-pyrrolidinocarbonyl                               624  Cl          2-F-phenyl                                                                               2-(methylsulfonyl)phenyl                            625  Cl          2-F-phenyl                                                                               4-morpholino                                        626  Cl          2-F-phenyl                                                                               2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                627  Cl          2-F-phenyl                                                                               4-morpholinocarbonyl                                628  Cl          2-F-phenyl                                                                               2-methyl-1-imidazolyl                               629  Cl          2-F-phenyl                                                                               5-methyl-1-imidazolyl                               630  Cl          2-F-phenyl                                                                               2-methylsulfonyl-1-imidazolyl                       631  Cl          2,6-diF-  2-(aminosulfonyl)phenyl                                              phenyl                                                        632  Cl          2,6-diF-  2-(methylaminosulfonyl)phenyl                                        phenyl                                                        633  Cl          2,6-diF-  1-pyrrolidinocarbonyl                                                phenyl                                                        634  Cl          2,6-diF-  2-(methylsulfonyl)phenyl                                             phenyl                                                        635  Cl          2,6-diF-  4-morpholino                                                         phenyl                                                        636  Cl          2,6-diF-  2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                                 phenyl                                                        637  Cl          2,6-diF-  4-morpholinocarbonyl                                                 phenyl                                                        638  Cl          2,6-diF-  2-methyl-1-imidazolyl                                                phenyl                                                        639  Cl          2,6-diF-  5-methyl-1-imidazolyl                                                phenyl                                                        640  Cl          2,6-diF-  2-methylsulfonyl-1-imidazolyl                                        phenyl                                                        641  F           phenyl    2-(aminosulfonyl)phenyl                             642  F           phenyl    2-(methylaminosulfonyl)phenyl                       643  F           phenyl    1-pyrrolidinocarbonyl                               644  F           phenyl    2-(methylsulfonyl)phenyl                            645  F           phenyl    4-morpholino                                        646  F           phenyl    2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                647  F           phenyl    4-morpholinocarbonyl                                648  F           phenyl    2-methyl-1-imidazolyl                               649  F           phenyl    5-methyl-1-imidazolyl                               650  F           phenyl    2-methylsulfonyl-1-imidazolyl                       651  F           2-pyridyl 2-(aminosulfonyl)phenyl                             652  F           2-pyridyl 2-(methylaminosulfonyl)phenyl                       653  F           2-pyridyl 1-pyrrolidinocarbonyl                               654  F           2-pyridyl 2-(methylsulfonyl)phenyl                            655  F           2-pyridyl 4-morpholino                                        656  F           2-pyridyl 2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                657  F           2-pyridyl 4-morpholinocarbonyl                                658  F           2-pyridyl 2-methyl-1-imidazolyl                               659  F           2-pyridyl 5-methyl-1-imidazolyl                               660  F           2-pyridyl 2-methylsulfonyl-1-imidazolyl                       661  F           3-pyridyl 2-(aminosulfonyl)phenyl                             662  F           3-pyridyl 2-(methylaminosulfonyl)phenyl                       663  F           3-pyridyl 1-pyrrolidinocarbonyl                               664  F           3-pyridyl 2-(methylsulfonyl)phenyl                            665  F           3-pyridyl 4-morpholino                                        666  F           3-pyridyl 2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                667  F           3-pyridyl 4-morpholinocarbonyl                                668  F           3-pyridyl 2-methyl-1-imidazolyl                               669  F           3-pyridyl 5-methyl-1-imidazolyl                               670  F           3-pyridyl 2-methylsulfonyl-1-imidazolyl                       671  F           2-pyrimidyl                                                                              2-(aminosulfonyl)phenyl                             672  F           2-pyrimidyl                                                                              2-(methylaminosulfonyl)phenyl                       673  F           2-pyrimidyl                                                                              1-pyrrolidinocarbonyl                               674  F           2-pyrimidyl                                                                              2-(methylsulfonyl)phenyl                            675  F           2-pyrimidyl                                                                              4-morpholino                                        676  F           2-pyrimidyl                                                                              2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                677  F           2-pyrimidyl                                                                              4-morpholinocarbonyl                                678  F           2-pyrimidyl                                                                              2-methyl-1-imidazolyl                               679  F           2-pyrimidyl                                                                              5-methyl-1-imidazolyl                               680  F           2-pyrimidyl                                                                              2-methylsulfonyl-1-imidazolyl                       681  F           5-pyrimidyl                                                                              2-(aminosulfonyl)phenyl                             682  F           5-pyrimidyl                                                                              2-(methylaminosulfonyl)phenyl                       683  F           5-pyrimidyl                                                                              1-pyrrolidinocarbonyl                               684  F           5-pyrimidyl                                                                              2-(methylsulfonyl)phenyl                            685  F           5-pyrimidyl                                                                              4-morpholino                                        686  F           5-pyrimidyl                                                                              2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                687  F           5-pyrimidyl                                                                              4-morpholinocarbonyl                                688  F           5-pyrimidyl                                                                              2-methyl-1-imidazolyl                               689  F           5-pyrimidyl                                                                              5-methyl-1-imidazolyl                               690  F           5-pyrimidyl                                                                              2-methylsulfonyl-1-imidazolyl                       691  F           2-Cl-phenyl                                                                              2-(aminosulfonyl)phenyl                             692  F           2-Cl-phenyl                                                                              2-(methylaminosulfonyl)phenyl                       693  F           2-Cl-phenyl                                                                              1-pyrrolidinocarbonyl                               694  F           2-Cl-phenyl                                                                              2-(methylsulfonyl)phenyl                            695  F           2-Cl-phenyl                                                                              4-morpholino                                        696  F           2-Cl-phenyl                                                                              2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                697  F           2-Cl-phenyl                                                                              4-morpholinocarbonyl                                698  F           2-Cl-phenyl                                                                              2-methyl-1-imidazolyl                               699  F           2-Cl-phenyl                                                                              5-methyl-1-imidazolyl                               700  F           2-Cl-phenyl                                                                              2-methylsulfonyl-1-imidazolyl                       701  F           2-F-phenyl                                                                               2-(aminosulfonyl)phenyl                             702  F           2-F-phenyl                                                                               2-(methylaminosulfonyl)phenyl                       703  F           2-F-phenyl                                                                               1-pyrrolidinocarbonyl                               704  F           2-F-phenyl                                                                               2-(methylsulfonyl)phenyl                            705  F           2-F-phenyl                                                                               4-morpholino                                        706  F           2-F-phenyl                                                                               2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                707  F           2-F-phenyl                                                                               4-morpholinocarbonyl                                708  F           2-F-phenyl                                                                               2-methyl-1-imidazolyl                               709  F           2-F-phenyl                                                                               5-methyl-1-imidazolyl                               710  F           2-F-phenyl                                                                               2-methylsulfonyl-1-imidazolyl                       711  F           2,6-diF-  2-(aminosulfonyl)phenyl                                              phenyl                                                        712  F           2,6-diF-  2-(methylaminosulfonyl)phenyl                                        phenyl                                                        713  F           2,6-diF-  1-pyrrolidinocarbonyl                                                phenyl                                                        714  F           2,6-diF-  2-(methylsulfonyl)phenyl                                             phenyl                                                        715  F           2,6-diF-  4-morpholino                                                         phenyl                                                        716  F           2,6-diF-  2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                                 phenyl                                                        717  F           2,6-diF-  4-morpholinocarbonyl                                                 phenyl                                                        718  F           2,6-diF-  2-methyl-1-imidazolyl                                                phenyl                                                        719  F           2,6-diF-  5-methyl-1-imidazolyl                                                phenyl                                                        720  F           2,6-diF-  2-methylsulfonyl-1-imidazolyl                                        phenyl                                                        721  CO.sub.2 CH.sub.3                                                                          phenyl    2-(aminosulfonyl)phenyl                             722  CO.sub.2 CH.sub.3                                                                          phenyl    2-(methylaminosulfonyl)phenyl                       723  CO.sub.2 CH.sub.3                                                                          phenyl    1-pyrrolidinocarbonyl                               724  CO.sub.2 CH.sub.3                                                                          phenyl    2-(methylsulfonyl)phenyl                            725  CO.sub.2 CH.sub.3                                                                          phenyl    4-morpholino                                        726  CO.sub.2 CH.sub.3                                                                          phenyl    2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                727  CO.sub.2 CH.sub.3                                                                          phenyl    4-morpholinocarbonyl                                728  CO.sub.2 CH.sub.3                                                                          phenyl    2-methyl-1-imidazolyl                               729  CO.sub.2 CH.sub.3                                                                          phenyl    5-methyl-1-imidazolyl                               730  CO.sub.2 CH.sub.3                                                                          phenyl    2-methylsulfonyl-1-imidazolyl                       731  CO.sub.2 CH.sub.3                                                                          2-pyridyl 2-(aminosulfonyl)phenyl                             732  CO.sub.2 CH.sub.3                                                                          2-pyridyl 2-(methylaminosulfonyl)phenyl                       733  CO.sub.2 CH.sub.3                                                                          2-pyridyl 1-pyrrolidinocarbonyl                               734  CO.sub.2 CH.sub.3                                                                          2-pyridyl 2-(methylsulfonyl)phenyl                            735  CO.sub.2 CH.sub.3                                                                          2-pyridyl 4-morpholino                                        736  CO.sub.2 CH.sub.3                                                                          2-pyridyl 2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                737  CO.sub.2 CH.sub.3                                                                          2-pyridyl 4-morpholinocarbonyl                                738  CO.sub.2 CH.sub.3                                                                          2-pyridyl 2-methyl-1-imidazolyl                               739  CO.sub.2 CH.sub.3                                                                          2-pyridyl 5-methyl-1-imidazolyl                               740  CO.sub.2 CH.sub.3                                                                          2-pyridyl 2-methylsulfonyl-1-imidazolyl                       741  CO.sub.2 CH.sub.3                                                                          3-pyridyl 2-(aminosulfonyl)phenyl                             742  CO.sub.2 CH.sub.3                                                                          3-pyridyl 2-(methylaminosulfonyl)phenyl                       743  CO.sub.2 CH.sub.3                                                                          3-pyridyl 1-pyrrolidinocarbonyl                               744  CO.sub.2 CH.sub.3                                                                          3-pyridyl 2-(methylsulfonyl)phenyl                            745  CO.sub.2 CH.sub.3                                                                          3-pyridyl 4-morpholino                                        746  CO.sub.2 CH.sub.3                                                                          3-pyridyl 2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                747  CO.sub.2 CH.sub.3                                                                          3-pyridyl 4-morpholinocarbonyl                                748  CO.sub.2 CH.sub.3                                                                          3-pyridyl 2-methyl-1-imidazolyl                               749  CO.sub.2 CH.sub.3                                                                          3-pyridyl 5-methyl-1-imidazolyl                               750  CO.sub.2 CH.sub.3                                                                          3-pyridyl 2-methylsulfonyl-1-imidazolyl                       751  CO.sub.2 CH.sub.3                                                                          2-pyrimidyl                                                                              2-(aminosulfonyl)phenyl                             752  CO.sub.2 CH.sub.3                                                                          2-pyrimidyl                                                                              2-(methylaminosulfonyl)phenyl                       753  CO.sub.2 CH.sub.3                                                                          2-pyrimidyl                                                                              1-pyrrolidinocarbonyl                               754  CO.sub.2 CH.sub.3                                                                          2-pyrimidyl                                                                              2-(methylsulfonyl)phenyl                            755  CO.sub.2 CH.sub.3                                                                          2-pyrimidyl                                                                              4-morpholino                                        756  CO.sub.2 CH.sub.3                                                                          2-pyrimidyl                                                                              2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                757  CO.sub.2 CH.sub.3                                                                          2-pyrimidyl                                                                              4-morpholinocarbonyl                                758  CO.sub.2 CH.sub.3                                                                          2-pyrimidyl                                                                              2-methyl-1-imidazolyl                               759  CO.sub.2 CH.sub.3                                                                          2-pyrimidyl                                                                              5-methyl-1-imidazolyl                               760  CO.sub.2 CH.sub.3                                                                          2-pyrimidyl                                                                              2-methylsulfonyl-1-imidazolyl                       761  CO.sub.2 CH.sub.3                                                                          5-pyrimidyl                                                                              2-(aminosulfonyl)phenyl                             762  CO.sub.2 CH.sub.3                                                                          5-pyrimidyl                                                                              2-(methylaminosulfonyl)phenyl                       763  CO.sub.2 CH.sub.3                                                                          5-pyrimidyl                                                                              1-pyrrolidinocarbonyl                               764  CO.sub.2 CH.sub.3                                                                          5-pyrimidyl                                                                              2-(methylsulfonyl)phenyl                            765  CO.sub.2 CH.sub.3                                                                          5-pyrimidyl                                                                              4-morpholino                                        766  CO.sub.2 CH.sub.3                                                                          5-pyrimidyl                                                                              2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                767  CO.sub.2 CH.sub.3                                                                          5-pyrimidyl                                                                              4-morpholinocarbonyl                                768  CO.sub.2 CH.sub.3                                                                          5-pyrimidyl                                                                              2-methyl-1-imidazolyl                               769  CO.sub.2 CH.sub.3                                                                          5-pyrimidyl                                                                              5-methyl-1-imidazolyl                               770  CO.sub.2 CH.sub.3                                                                          5-pyrimidyl                                                                              2-methylsulfonyl-1-imidazolyl                       771  CO.sub.2 CH.sub.3                                                                          2-Cl-phenyl                                                                              2-(aminosulfonyl)phenyl                             772  CO.sub.2 CH.sub.3                                                                          2-Cl-phenyl                                                                              2-(methylaminosulfonyl)phenyl                       773  CO.sub.2 CH.sub.3                                                                          2-Cl-phenyl                                                                              1-pyrrolidinocarbonyl                               774  CO.sub.2 CH.sub.3                                                                          2-Cl-phenyl                                                                              2-(methylsulfonyl)phenyl                            775  CO.sub.2 CH.sub.3                                                                          2-Cl-phenyl                                                                              4-morpholino                                        776  CO.sub.2 CH.sub.3                                                                          2-Cl-phenyl                                                                              2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                777  CO.sub.2 CH.sub.3                                                                          2-Cl-phenyl                                                                              4-morpholinocarbonyl                                778  CO.sub.2 CH.sub.3                                                                          2-Cl-phenyl                                                                              2-methyl-1-imidazolyl                               779  CO.sub.2 CH.sub.3                                                                          2-Cl-phenyl                                                                              5-methyl-1-imidazolyl                               780  CO.sub.2 CH.sub.3                                                                          2-Cl-phenyl                                                                              2-methylsulfonyl-1-imidazolyl                       781  CO.sub.2 CH.sub.3                                                                          2-F-phenyl                                                                               2-(aminosulfonyl)phenyl                             782  CO.sub.2 CH.sub.3                                                                          2-F-phenyl                                                                               2-(methylaminosulfonyl)phenyl                       783  CO.sub.2 CH.sub.3                                                                          2-F-phenyl                                                                               1-pyrrolidinocarbonyl                               784  CO.sub.2 CH.sub.3                                                                          2-F-phenyl                                                                               2-(methylsulfonyl)phenyl                            785  CO.sub.2 CH.sub.3                                                                          2-F-phenyl                                                                               4-morpholino                                        786  CO.sub.2 CH.sub.3                                                                          2-F-phenyl                                                                               2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                787  CO.sub.2 CH.sub.3                                                                          2-F-phenyl                                                                               4-morpholinocarbonyl                                788  CO.sub.2 CH.sub.3                                                                          2-F-phenyl                                                                               2-methyl-1-imidazolyl                               789  CO.sub.2 CH.sub.3                                                                          2-F-phenyl                                                                               5-methyl-1-imidazolyl                               790  CO.sub.2 CH.sub.3                                                                          2-F-phenyl                                                                               2-methylsulfonyl-1-imidazolyl                       791  CO.sub.2 CH.sub.3                                                                          2,6-diF-  2-(aminosulfonyl)phenyl                                              phenyl                                                        792  CO.sub.2 CH.sub.3                                                                          2,6-diF-  2-(methylaminosulfonyl)phenyl                                        phenyl                                                        793  CO.sub.2 CH.sub.3                                                                          2,6-diF-  1-pyrrolidinocarbonyl                                                phenyl                                                        794  CO.sub.2 CH.sub.3                                                                          2,6-diF-  2-(methylsulfonyl)phenyl                                             phenyl                                                        795  CO.sub.2 CH.sub.3                                                                          2,6-diF-  4-morpholino                                                         phenyl                                                        796  CO.sub.2 CH.sub.3                                                                          2,6-diF-  2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                                 phenyl                                                        797  CO.sub.2 CH.sub.3                                                                          2,6-diF-  4-morpholinocarbonyl                                                 phenyl                                                        798  CO.sub.2 CH.sub.3                                                                          2,6-diF-  2-methyl-1-imidazolyl                                                phenyl                                                        799  CO.sub.2 CH.sub.3                                                                          2,6-diF-  5-methyl-1-imidazolyl                                                phenyl                                                        800  CO.sub.2 CH.sub.3                                                                          2,6-diF-  2-methylsulfonyl-1-imidazolyl                                        phenyl                                                        801  CH.sub.2 OCH.sub.3                                                                         phenyl    2-(aminosulfonyl)phenyl                             802  CH.sub.2 OCH.sub.3                                                                         phenyl    2-(methylaminosulfonyl)phenyl                       803  CH.sub.2 OCH.sub.3                                                                         phenyl    1-pyrrolidinocarbonyl                               804  CH.sub.2 OCH.sub.3                                                                         phenyl    2-(methylsulfonyl)phenyl                            805  CH.sub.2 OCH.sub.3                                                                         phenyl    4-morpholino                                        806  CH.sub.2 OCH.sub.3                                                                         phenyl    2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                807  CH.sub.2 OCH.sub.3                                                                         phenyl    4-morpholinocarbonyl                                808  CH.sub.2 OCH.sub.3                                                                         phenyl    2-methyl-1-imidazolyl                               809  CH.sub.2 OCH.sub.3                                                                         phenyl    5-methyl-1-imidazolyl                               810  CH.sub.2 OCH.sub.3                                                                         phenyl    2-methylsulfonyl-1-imidazolyl                       811  CH.sub.2 OCH.sub.3                                                                         2-pyridyl 2-(aminosulfonyl)phenyl                             812  CH.sub.2 OCH.sub.3                                                                         2-pyridyl 2-(methylaminosulfonyl)phenyl                       813  CH.sub.2 OCH.sub.3                                                                         2-pyridyl 1-pyrrolidinocarbonyl                               814  CH.sub.2 OCH.sub.3                                                                         2-pyridyl 2-(methylsulfonyl)phenyl                            815  CH.sub.2 OCH.sub.3                                                                         2-pyridyl 4-morpholino                                        816  CH.sub.2 OCH.sub.3                                                                         2-pyridyl 2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                817  CH.sub.2 OCH.sub.3                                                                         2-pyridyl 4-morpholinocarbonyl                                818  CH.sub.2 OCH.sub.3                                                                         2-pyridyl 2-methyl-1-imidazolyl                               819  CH.sub.2 OCH.sub.3                                                                         2-pyridyl 5-methyl-1-imidazolyl                               820  CH.sub.2 OCH.sub.3                                                                         2-pyridyl 2-methylsulfonyl-1-imidazolyl                       821  CH.sub.2 OCH.sub.3                                                                         3-pyridyl 2-(aminosulfonyl)phenyl                             822  CH.sub.2 OCH.sub.3                                                                         3-pyridyl 2-(methylaminosulfonyl)phenyl                       823  CH.sub.2 OCH.sub.3                                                                         3-pyridyl 1-pyrrolidinocarbonyl                               824  CH.sub.2 OCH.sub.3                                                                         3-pyridyl 2-(methylsulfonyl)phenyl                            825  CH.sub.2 OCH.sub.3                                                                         3-pyridyl 4-morpholino                                        826  CH.sub.2 OCH.sub.3                                                                         3-pyridyl 2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                827  CH.sub.2 OCH.sub.3                                                                         3-pyridyl 4-morpholinocarbonyl                                828  CH.sub.2 OCH.sub.3                                                                         3-pyridyl 2-methyl-1-imidazolyl                               829  CH.sub.2 OCH.sub.3                                                                         3-pyridyl 5-methyl-1-imidazolyl                               830  CH.sub.2 OCH.sub.3                                                                         3-pyridyl 2-methylsulfonyl-1-imidazolyl                       831  CH.sub.2 OCH.sub.3                                                                         2-pyrimidyl                                                                              2-(aminosulfonyl)phenyl                             832  CH.sub.2 OCH.sub.3                                                                         2-pyrimidyl                                                                              2-(methylaminosulfonyl)phenyl                       833  CH.sub.2 OCH.sub.3                                                                         2-pyrimidyl                                                                              1-pyrrolidinocarbonyl                               834  CH.sub.2 OCH.sub.3                                                                         2-pyrimidyl                                                                              2-(methylsulfonyl)phenyl                            835  CH.sub.2 OCH.sub.3                                                                         2-pyrimidyl                                                                              4-morpholino                                        836  CH.sub.2 OCH.sub.3                                                                         2-pyrimidyl                                                                              2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                837  CH.sub.2 OCH.sub.3                                                                         2-pyrimidyl                                                                              4-morpholinocarbonyl                                838  CH.sub.2 OCH.sub.3                                                                         2-pyrimidyl                                                                              2-methyl-1-imidazolyl                               839  CH.sub.2 OCH.sub.3                                                                         2-pyrimidyl                                                                              5-methyl-1-imidazolyl                               840  CH.sub.2 OCH.sub.3                                                                         2-pyrimidyl                                                                              2-methylsulfonyl-1-imidazolyl                       841  CH.sub.2 OCH.sub.3                                                                         5-pyrimidyl                                                                              2-(aminosulfonyl)phenyl                             842  CH.sub.2 OCH.sub.3                                                                         5-pyrimidyl                                                                              2-(methylaminosulfonyl)phenyl                       843  CH.sub.2 OCH.sub.3                                                                         5-pyrimidyl                                                                              1-pyrrolidinocarbonyl                               844  CH.sub.2 OCH.sub.3                                                                         5-pyrimidyl                                                                              2-(methylsulfonyl)phenyl                            845  CH.sub.2 OCH.sub.3                                                                         5-pyrimidyl                                                                              4-morpholino                                        846  CH.sub.2 OCH.sub.3                                                                         5-pyrimidyl                                                                              2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                847  CH.sub.2 OCH.sub.3                                                                         5-pyrimidyl                                                                              4-morpholinocarbonyl                                848  CH.sub.2 OCH.sub.3                                                                         5-pyrimidyl                                                                              2-methyl-1-imidazolyl                               849  CH.sub.2 OCH.sub.3                                                                         5-pyrimidyl                                                                              5-methyl-1-imidazolyl                               850  CH.sub.2 OCH.sub.3                                                                         5-pyrimidyl                                                                              2-methylsulfonyl-1-imidazolyl                       851  CH.sub.2 OCH.sub.3                                                                         2-Cl-phenyl                                                                              2-(aminosulfonyl)phenyl                             852  CH.sub.2 OCH.sub.3                                                                         2-Cl-phenyl                                                                              2-(methylaminosulfonyl)phenyl                       853  CH.sub.2 OCH.sub.3                                                                         2-Cl-phenyl                                                                              1-pyrrolidinocarbonyl                               854  CH.sub.2 OCH.sub.3                                                                         2-Cl-phenyl                                                                              2-(methylsulfonyl)phenyl                            855  CH.sub.2 OCH.sub.3                                                                         2-Cl-phenyl                                                                              4-morpholino                                        856  CH.sub.2 OCH.sub.3                                                                         2-Cl-phenyl                                                                              2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                857  CH.sub.2 OCH.sub.3                                                                         2-Cl-phenyl                                                                              4-morpholinocarbonyl                                858  CH.sub.2 OCH.sub.3                                                                         2-Cl-phenyl                                                                              2-methyl-1-imidazolyl                               859  CH.sub.2 OCH.sub.3                                                                         2-Cl-phenyl                                                                              5-methyl-1-imidazolyl                               860  CH.sub.2 OCH.sub.3                                                                         2-Cl-phenyl                                                                              2-methylsulfonyl-1-imidazolyl                       861  CH.sub.2 OCH.sub.3                                                                         2-F-phenyl                                                                               2-(aminosulfonyl)phenyl                             862  CH.sub.2 OCH.sub.3                                                                         2-F-phenyl                                                                               2-(methylaminosulfonyl)phenyl                       863  CH.sub.2 OCH.sub.3                                                                         2-F-phenyl                                                                               1-pyrrolidinocarbonyl                               864  CH.sub.2 OCH.sub.3                                                                         2-F-phenyl                                                                               2-(methylsulfonyl)phenyl                            865  CH.sub.2 OCH.sub.3                                                                         2-F-phenyl                                                                               4-morpholino                                        866  CH.sub.2 OCH.sub.3                                                                         2-F-phenyl                                                                               2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                867  CH.sub.2 OCH.sub.3                                                                         2-F-phenyl                                                                               4-morpholinocarbonyl                                868  CH.sub.2 OCH.sub.3                                                                         2-F-phenyl                                                                               2-methyl-1-imidazolyl                               869  CH.sub.2 OCH.sub.3                                                                         2-F-phenyl                                                                               5-methyl-1-imidazolyl                               870  CH.sub.2 OCH.sub.3                                                                         2-F-phenyl                                                                               2-methylsulfonyl-1-imidazolyl                       871  CH.sub.2 OCH.sub.3                                                                         2,6-diF-  2-(aminosulfonyl)phenyl                                              phenyl                                                        872  CH.sub.2 OCH.sub.3                                                                         2,6-diF-  2-(methylaminosulfonyl)phenyl                                        phenyl                                                        873  CH.sub.2 OCH.sub.3                                                                         2,6-diF-  1-pyrrolidinocarbonyl                                                phenyl                                                        874  CH.sub.2 OCH.sub.3                                                                         2,6-diF-  2-(methylsulfonyl)phenyl                                             phenyl                                                        875  CH.sub.2 OCH.sub.3                                                                         2,6-diF-  4-morpholino                                                         phenyl                                                        876  CH.sub.2 OCH.sub.3                                                                         2,6-diF-  2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                                 phenyl                                                        877  CH.sub.2 OCH.sub.3                                                                         2,6-diF-  4-morpholinocarbonyl                                                 phenyl                                                        878  CH.sub.2 OCH.sub.3                                                                         2,6-diF-  2-methyl-1-imidazolyl                                                phenyl                                                        879  CH.sub.2 OCH.sub.3                                                                         2,6-diF-  5-methyl-1-imidazolyl                                                phenyl                                                        880  CH.sub.2 OCH.sub.3                                                                         2,6-diF-  2-methylsulfonyl-1-imidazolyl                                        phenyl                                                        881  CONH.sub.2  phenyl    2-(aminosulfonyl)phenyl                             882  CONH.sub.2  phenyl    2-(methylaminosulfonyl)phenyl                       883  CONH.sub.2  phenyl    1-pyrrolidinocarbonyl                               884  CONH.sub.2  phenyl    2-(methylsulfonyl)phenyl                            885  CONH.sub.2  phenyl    4-morpholino                                        886  CONH.sub.2  phenyl    2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                887  CONH.sub.2  phenyl    4-morpholinocarbonyl                                888  CONH.sub.2  phenyl    2-methyl-1-imidazolyl                               889  CONH.sub.2  phenyl    5-methyl-1-imidazolyl                               890  CONH.sub.2  phenyl    2-methylsulfonyl-1-imidazolyl                       891  CONH.sub.2  2-pyridyl 2-(aminosulfonyl)phenyl                             892  CONH.sub.2  2-pyridyl 2-(methylaminosulfonyl)phenyl                       893  CONH.sub.2  2-pyridyl 1-pyrrolidinocarbonyl                               894  CONH.sub.2  2-pyridyl 2-(methylsulfonyl)phenyl                            895  CONH.sub.2  2-pyridyl 4-morpholino                                        896  CONH.sub.2  2-pyridyl 2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                897  CONH.sub.2  2-pyridyl 4-morpholinocarbonyl                                898  CONH.sub.2  2-pyridyl 2-methyl-1-imidazolyl                               899  CONH.sub.2  2-pyridyl 5-methyl-1-imidazolyl                               900  CONH.sub.2  2-pyridyl 2-methylsulfonyl-1-imidazolyl                       901  CONH.sub.2  3-pyridyl 2-(aminosulfonyl)phenyl                             902  CONH.sub.2  3-pyridyl 2-(methylaminosulfonyl)phenyl                       903  CONH.sub.2  3-pyridyl 1-pyrrolidinocarbonyl                               904  CONH.sub.2  3-pyridyl 2-(methylsulfonyl)phenyl                            905  CONH.sub.2  3-pyridyl 4-morpholino                                        906  CONH.sub.2  3-pyridyl 2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                907  CONH.sub.2  3-pyridyl 4-morpholinocarbonyl                                908  CONH.sub.2  3-pyridyl 2-methyl-1-imidazolyl                               909  CONH.sub.2  3-pyridyl 5-methyl-1-imidazolyl                               910  CONH.sub.2  3-pyridyl 2-methylsulfonyl-1-imidazolyl                       911  CONH.sub.2  2-pyrimidyl                                                                              2-(aminosulfonyl)phenyl                             912  CONH.sub.2  2-pyrimidyl                                                                              2-(methylaminosulfonyl)phenyl                       913  CONH.sub.2  2-pyrimidyl                                                                              1-pyrrolidinocarbonyl                               914  CONH.sub.2  2-pyrimidyl                                                                              2-(methylsulfonyl)phenyl                            915  CONH.sub.2  2-pyrimidyl                                                                              4-morpholino                                        916  CONH.sub.2  2-pyrimidyl                                                                              2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                917  CONH.sub.2  2-pyrimidyl                                                                              4-morpholinocarbonyl                                918  CONH.sub.2  2-pyrimidyl                                                                              2-methyl-1-imidazolyl                               919  CONH.sub.2  2-pyrimidyl                                                                              5-methyl-1-imidazolyl                               920  CONH.sub.2  2-pyrimidyl                                                                              2-methylsulfonyl-1-imidazolyl                       921  CONH.sub.2  5-pyrimidyl                                                                              2-(aminosulfonyl)phenyl                             922  CONH.sub.2  5-pyrimidyl                                                                              2-(methylaminosulfonyl)phenyl                       923  CONH.sub.2  5-pyrimidyl                                                                              1-pyrrolidinocarbonyl                               924  CONH.sub.2  5-pyrimidyl                                                                              2-(methylsulfonyl)phenyl                            925  CONH.sub.2  5-pyrimidyl                                                                              4-morpholino                                        926  CONH.sub.2  5-pyrimidyl                                                                              2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                927  CONH.sub.2  5-pyrimidyl                                                                              4-morpholinocarbonyl                                928  CONH.sub.2  5-pyrimidyl                                                                              2-methyl-1-imidazolyl                               929  CONH.sub.2  5-pyrimidyl                                                                              5-methyl-1-imidazolyl                               930  CONH.sub.2  5-pyrimidyl                                                                              2-methylsulfonyl-1-imidazolyl                       931  CONH.sub.2  2-Cl-phenyl                                                                              2-(aminosulfonyl)phenyl                             932  CONH.sub.2  2-Cl-phenyl                                                                              2-(methylaminosulfonyl)phenyl                       933  CONH.sub.2  2-Cl-phenyl                                                                              1-pyrrolidinocarbonyl                               934  CONH.sub.2  2-Cl-phenyl                                                                              2-(methylsulfonyl)phenyl                            935  CONH.sub.2  2-Cl-phenyl                                                                              4-morpholino                                        936  CONH.sub.2  2-Cl-phenyl                                                                              2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                937  CONH.sub.2  2-Cl-phenyl                                                                              4-morpholinocarbonyl                                938  CONH.sub.2  2-Cl-phenyl                                                                              2-methyl-1-imidazolyl                               939  CONH.sub.2  2-Cl-phenyl                                                                              5-methyl-1-imidazolyl                               940  CONH.sub.2  2-Cl-phenyl                                                                              2-methylsulfonyl-1-imidazolyl                       941  CONH.sub.2  2-F-phenyl                                                                               2-(aminosulfonyl)phenyl                             942  CONH.sub.2  2-F-phenyl                                                                               2-(methylaminosulfonyl)phenyl                       943  CONH.sub.2  2-F-phenyl                                                                               1-pyrrolidinocarbonyl                               944  CONH.sub.2  2-F-phenyl                                                                               2-(methylsulfonyl)phenyl                            945  CONH.sub.2  2-F-phenyl                                                                               4-morpholino                                        946  CONH.sub.2  2-F-phenyl                                                                               2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                947  CONH.sub.2  2-F-phenyl                                                                               4-morpholinocarbonyl                                948  CONH.sub.2  2-F-phenyl                                                                               2-methyl-1-imidazolyl                               949  CONH.sub.2  2-F-phenyl                                                                               5-methyl-1-imidazolyl                               950  CONH.sub.2  2-F-phenyl                                                                               2-methylsulfonyl-1-imidazolyl                       951  CONH.sub.2  2,6-diF-  2-(aminosulfonyl)phenyl                                              phenyl                                                        952  CONH.sub.2  2,6-diF-  2-(methylaminosulfonyl)phenyl                                        phenyl                                                        953  CONH.sub.2  2,6-diF-  1-pyrrolidinocarbonyl                                                phenyl                                                        954  CONH.sub.2  2,6-diF-  2-(methylsulfonyl)phenyl                                             phenyl                                                        955  CONH.sub.2  2,6-diF-  4-morpholino                                                         phenyl                                                        956  CONH.sub.2  2,6-diF-  2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                                 phenyl                                                        957  CONH.sub.2  2,6-diF-  4-morpholinocarbonyl                                                 phenyl                                                        958  CONH.sub.2  2,6-diF-  2-methyl-1-imidazolyl                                                phenyl                                                        959  CONH.sub.2  2,6-diF-  5-methyl-1-imidazolyl                                                phenyl                                                        960  CONH.sub.2  2,6-diF-  2-methylsulfonyl-1-imidazolyl                                        phenyl                                                        ______________________________________                                          For each example, DE is:                                                       (A) pyridin4-yl-CH.sub.2,                                                      (B) 2amino-pyrimidin-4-yl,                                                     (C) 6amino-pyridin-2-yl,                                                       (D) 3amidino-4-F-phenyl, or                                                    (E) Namidino-3-piperidinyl.                                              

                  TABLE 7                                                          ______________________________________                                          ##STR263##                                                                     ##STR264##                                                                    Ex #    A            B                                                         ______________________________________                                          1      phenyl       2-(aminosulfonyl)phenyl                                    2      phenyl       2-(methylaminosulfonyl)phenyl                              3      phenyl       1-pyrrolidinocarbonyl                                      4      phenyl       2-(methylsulfonyl)phenyl                                   5      phenyl       4-morpholino                                               6      phenyl       2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                       7      phenyl       4-morpholinocarbonyl                                       8      phenyl       2-methyl-1-imidazolyl                                      9      phenyl       5-methyl-1-imidazolyl                                     10      phenyl       2-methylsulfonyl-1-imidazolyl                             11      2-pyridyl    2-(aminosulfonyl)phenyl                                   12      2-pyridyl    2-(methylaminosulfonyl)phenyl                             13      2-pyridyl    1-pyrrolidinocarbonyl                                     14      2-pyridyl    2-(methylsulfonyl)phenyl                                  15      2-pyridyl    4-morpholino                                              16      2-pyridyl    2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                      17      2-pyridyl    4-morpholinocarbonyl                                      18      2-pyridyl    2-methyl-1-imidazolyl                                     19      2-pyridyl    5-methyl-1-imidazolyl                                     20      2-pyridyl    2-methylsulfonyl-1-imidazolyl                             21      3-pyridyl    2-(aminosulfonyl)phenyl                                   22      3-pyridyl    2-(methylaminosulfonyl)phenyl                             23      3-pyridyl    1-pyrrolidinocarbonyl                                     24      3-pyridyl    2-(methylsulfonyl)phenyl                                  25      3-pyridyl    4-morpholino                                              26      3-pyridyl    2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                      27      3-pyridyl    4-morpholinocarbonyl                                      28      3-pyridyl    2-methyl-1-imidazolyl                                     29      3-pyridyl    5-methyl-1-imidazolyl                                     30      3-pyridyl    2-methylsulfonyl-1-imidazolyl                             31      2-pyrimidyl  2-(aminosulfonyl)phenyl                                   32      2-pyrimidyl  2-(methylaminosulfonyl)phenyl                             33      2-pyrimidyl  1-pyrrolidinocarbonyl                                     34      2-pyrimidyl  2-(methylsulfonyl)phenyl                                  35      2-pyrimidyl  4-morpholino                                              36      2-pyrimidyl  2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                      37      2-pyrimidyl  4-morpholinocarbonyl                                      38      2-pyrimidyl  2-methyl-1-imidazolyl                                     39      2-pyrimidyl  5-methyl-1-imidazolyl                                     40      2-pyrimidyl  2-methylsulfonyl-1-imidazolyl                             41      5-pyrimidyl  2-(aminosulfonyl)phenyl                                   42      5-pyrimidyl  2-(methylaminosulfonyl)phenyl                             43      5-pyrimidyl  1-pyrrolidinocarbonyl                                     44      5-pyrimidyl  2-(methylsulfonyl)phenyl                                  45      5-pyrimidyl  4-morpholino                                              46      5-pyrimidyl  2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                      47      5-pyrimidyl  4-morpholinocarbonyl                                      48      5-pyrimidyl  2-methyl-1-imidazolyl                                     49      5-pyrimidyl  5-methyl-1-imidazolyl                                     50      5-pyrimidyl  2-methylsulfonyl-1-imidazolyl                             51      2-Cl-phenyl  2-(aminosulfonyl)phenyl                                   52      2-Cl-phenyl  2-(methylaminosulfonyl)phenyl                             53      2-Cl-phenyl  1-pyrrolidinocarbonyl                                     54      2-Cl-phenyl  2-(methylsulfonyl)phenyl                                  55      2-Cl-phenyl  4-morpholino                                              56      2-Cl-phenyl  2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                      57      2-Cl-phenyl  4-morpholinocarbonyl                                      58      2-Cl-phenyl  2-methyl-1-imidazolyl                                     59      2-Cl-phenyl  5-methyl-1-imidazolyl                                     60      2-Cl-phenyl  2-methylsulfonyl-1-imidazolyl                             61      2-F-phenyl   2-(aminosulfonyl)phenyl                                   62      2-F-phenyl   2-(methylaminosulfonyl)phenyl                             63      2-F-phenyl   1-pyrrolidinocarbonyl                                     64      2-F-phenyl   2-(methylsulfonyl)phenyl                                  65      2-F-phenyl   4-morpholino                                              66      2-F-phenyl   2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                      67      2-F-phenyl   4-morpholinocarbonyl                                      68      2-F-phenyl   2-methyl-1-imidazolyl                                     69      2-F-phenyl   5-methyl-1-imidazolyl                                     70      2-F-phenyl   2-methylsulfonyl-1-imidazolyl                             71      2,6-diF-phenyl                                                                              2-(aminosulfonyl)phenyl                                   72      2,6-diF-phenyl                                                                              2-(methylaminosulfonyl)phenyl                             73      2,6-diF-phenyl                                                                              1-pyrrolidinocarbonyl                                     74      2,6-diF-phenyl                                                                              2-(methylsulfonyl)phenyl                                  75      2,6-diF-phenyl                                                                              4-morpholino                                              76      2,6-diF-phenyl                                                                              2-(1'-CF.sub.3 -tetrazol-2-yl)phenyl                      77      2,6-diF-phenyl                                                                              4-morpholinocarbonyl                                      78      2,6-diF-phenyl                                                                              2-methyl-1-imidazolyl                                     79      2,6-diF-phenyl                                                                              5-methyl-1-imidazolyl                                     80      2,6-diF-phenyl                                                                              2-methylsulfonyl-1-imidazolyl                             ______________________________________                                          For each example, DE is:                                                       (A) pyridin4-yl-CH.sub.2,                                                      (B) 2amino-pyrimidin-4-yl,                                                     (C) 6amino-pyridin-2-yl,                                                       (D) 3amidino-4-F-phenyl, or                                                    (E) Namidino-3-piperidinyl.                                              

Utility

The compounds of this invention are useful as anticoagulants for the treatment or prevention of thromboembolic disorders in mammals. The term "thromboembolic disorders" as used herein includes arterial or venous cardiovascular or cerebrovascular thromboembolic disorders, including, for example, unstable angina, first or recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary and cerebral arterial thrombosis, cerebral embolism, kidney embolisms, and pulmonary embolisms. The anticoagulant effect of compounds of the present invention is believed to be due to inhibition of factor Xa or thrombin.

The effectiveness of compounds of the present invention as inhibitors of factor Xa was determined using purified human factor Xa and synthetic substrate. The rate of factor Xa hydrolysis of chromogenic substrate S2222 (Kabi Pharmacia, Franklin, Ohio) was measured both in the absence and presence of compounds of the present invention. Hydrolysis of the substrate resulted in the release of pNA, which was monitored spectrophotometrically by measuring the increase in absorbance at 405 nM. A decrease in the rate of absorbance change at 405 nm in the presence of inhibitor is indicative of enzyme inhibition. The results of this assay are expressed as inhibitory constant, K_(i).

Factor Xa determinations were made in 0.10 M sodium phosphate buffer, pH 7.5, containing 0.20 M NaCl, and 0.5% PEG 8000. The Michaelis constant, K_(m), for substrate hydrolysis was determined at 25° C. using the method of Lineweaver and Burk. Values of K_(i) were determined by allowing 0.2-0.5 nM human factor Xa (Enzyme Research Laboratories, South Bend, Ind.) to react with the substrate (0.20 mM-1 mM) in the presence of inhibitor. Reactions were allowed to go for 30 minutes and the velocities (rate of absorbance change vs time) were measured in the time frame of 25-30 minutes. The following relationship was used to calculate K_(i) values:

    (v.sub.o -v.sub.s)/v.sub.s =I/(K.sub.i (1+S/K.sub.m))

where:

v_(o) is the velocity of the control in the absence of inhibitor;

v_(s) is the velocity in the presence of inhibitor;

I is the concentration of inhibitor;

K_(i) is the dissociation constant of the enzyme:inhibitor complex;

S is the concentration of substrate;

K_(m) is the Michaelis constant.

Using the methodology described above, a number of compounds of the present invention were found to exhibit a K_(i) of ≦10 μM, thereby confirming the utility of the compounds of the present invention as effective Xa inhibitors.

The antithrombotic effect of compounds of the present invention can be demonstrated in a rabbit arterio-venous (AV) shunt thrombosis model. In this model, rabbits weighing 2-3 kg anesthetized with a mixture of xylazine (10 mg/kg i.m.) and ketamine (50 mg/kg i.m.) are used. A saline-filled AV shunt device is connected between the femoral arterial and the femoral venous cannulae. The AV shunt device consists of a piece of 6-cm tygon tubing which contains a piece of silk thread. Blood will flow from the femoral artery via the AV-shunt into the femoral vein. The exposure of flowing blood to a silk thread will induce the formation of a significant thrombus. After forty minutes, the shunt is disconnected and the silk thread covered with thrombus is weighed. Test agents or vehicle will be given (i.v., i.p., s.c., or orally) prior to the opening of the AV shunt. The percentage inhibition of thrombus formation is determined for each treatment group. The ID50 values (dose which produces 50% inhibition of thrombus formation) are estimated by linear regression.

The compounds of formula (I) may also be useful as inhibitors of serine proteases, notably human thrombin, plasma kallikrein and plasmin. Because of their inhibitory action, these compounds are indicated for use in the prevention or treatment of physiological reactions, blood coagulation and inflammation, catalyzed by the aforesaid class of enzymes. Specifically, the compounds have utility as drugs for the treatment of diseases arising from elevated thrombin activity such as myocardial infarction, and as reagents used as anticoagulants in the processing of blood to plasma for diagnostic and other commercial purposes.

Some compounds of the present invention were shown to be direct acting inhibitors of the serine protease thrombin by their ability to inhibit the cleavage of small molecule substrates by thrombin in a purified system. In vitro inhibition constants were determined by the method described by Kettner et al. in J. Biol. Chem. 265, 18289-18297 (1990), herein incorporated by reference. In these assays, thrombin-mediated hydrolysis of the chromogenic substrate S2238 (Helena Laboratories, Beaumont, Tex.) was monitored spectrophotometrically. Addition of an inhibitor to the assay mixture results in decreased absorbance and is indicative of thrombin inhibition. Human thrombin (Enzyme Research Laboratories, Inc., South Bend, Ind.) at a concentration of 0.2 nM in 0.10 M sodium phosphate buffer, pH 7.5, 0.20 M NaCl, and 0.5% PEG 6000, was incubated with various substrate concentrations ranging from 0.20 to 0.02 mm. After 25 to 30 minutes of incubation, thrombin activity was assayed by monitoring the rate of increase in absorbance at 405 nm which arises owing to substrate hydrolysis. Inhibition constants were derived from reciprocal plots of the reaction velocity as a function of substrate concentration using the standard method of Lineweaver and Burk. Using the methodology described above, some compounds of this invention were evaluated and found to exhibit a K_(i) of less than 10 μm, thereby confirming the utility of the compounds of the present invention as effective thrombin inhibitors.

The compounds of the present invention can be administered alone or in combination with one or more additional therapeutic agents. These include other anti-coagulant or coagulation inhibitory agents, anti-platelet or platelet inhibitory agents, thrombin inhibitors, or thrombolytic or fibrinolytic agents.

The compounds are administered to a mammal in a therapeutically effective amount. By "therapeutically effective amount" it is meant an amount of a compound of Formula I that, when administered alone or in combination with an additional therapeutic agent to a mammal, is effective to prevent or ameliorate the thromboembolic disease condition or the progression of the disease.

By "administered in combination" or "combination therapy" it is meant that the compound of Formula I and one or more additional therapeutic agents are administered concurrently to the mammal being treated. When administered in combination each component may be administered at the same time or sequentially in any order at different points in time. Thus, each component may be administered separately but sufficiently closely in time so as to provide the desired therapeutic effect. Other anticoagulant agents (or coagulation inhibitory agents) that may be used in combination with the compounds of this invention include warfarin and heparin, as well as other factor Xa inhibitors such as those described in the publications identified above under Background of the Invention.

The term anti-platelet agents (or platelet inhibitory agents), as used herein, denotes agents that inhibit platelet function such as by inhibiting the aggregation, adhesion or granular secretion of platelets. Such agents include, but are not limited to, the various known non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, sulindac, indomethacin, mefenamate, droxicam, diclofenac, sulfinpyrazone, and piroxicam, including pharmaceutically acceptable salts or prodrugs thereof. Of the NSAIDS, aspirin (acetylsalicyclic acid or ASA), and piroxicam are preferred. Other suitable anti-platelet agents include ticlopidine, including pharmaceutically acceptable salts or prodrugs thereof. Ticlopidine is also a preferred compound since it is known to be gentle on the gastro-intestinal tract in use. Still other suitable platelet inhibitory agents include IIb/IIIa antagonists, thromboxane-A2-receptor antagonists and thromboxane-A2-synthetase inhibitors, as well as pharmaceutically acceptable salts or prodrugs thereof.

The term thrombin inhibitors (or anti-thrombin agents), as used herein, denotes inhibitors of the serine protease thrombin. By inhibiting thrombin, various thrombin-mediated processes, such as thrombin-mediated platelet activation (that is, for example, the aggregation of platelets, and/or the granular secretion of plasminogen activator inhibitor-1 and/or serotonin) and/or fibrin formation are disrupted. A number of thrombin inhibitors are known to one of skill in the art and these inhibitors are contemplated to be used in combination with the present compounds. Such inhibitors include, but are not limited to, boroarginine derivatives, boropeptides, heparins, hirudin and argatroban, including pharmaceutically acceptable salts and prodrugs thereof. Boroarginine derivatives and boropeptides include N-acetyl and peptide derivatives of boronic acid, such as C-terminal a-aminoboronic acid derivatives of lysine, ornithine, arginine, homoarginine and corresponding isothiouronium analogs thereof. The term hirudin, as used herein, includes suitable derivatives or analogs of hirudin, referred to herein as hirulogs, such as disulfatohirudin. Boropeptide thrombin inhibitors include compounds described in Kettner et al., U.S. Pat. No. 5,187,157 and European Patent Application Publication Number 293 881 A2, the disclosures of which are hereby incorporated herein by reference. Other suitable boroarginine derivatives and boropeptide thrombin inhibitors include those disclosed in PCT Application Publication Number 92/07869 and European Patent Application Publication Number 471,651 A2, the disclosures of which are hereby incorporated herein by reference.

The term thrombolytics (or fibrinolytic) agents (or thrombolytics or fibrinolytics), as used herein, denotes agents that lyse blood clots (thrombi). Such agents include tissue plasminogen activator, anistreplase, urokinase or streptokinase, including pharmaceutically acceptable salts or prodrugs thereof. The term anistreplase, as used herein, refers to anisoylated plasminogen streptokinase activator complex, as described, for example, in European Patent Application No. 028,489, the disclosure of which is hereby incorporated herein by reference herein. The term urokinase, as used herein, is intended to denote both dual and single chain urokinase, the latter also being referred to herein as prourokinase.

Administration of the compounds of Formula I of the invention in combination with such additional therapeutic agent, may afford an efficacy advantage over the compounds and agents alone, and may do so while permitting the use of lower doses of each. A lower dosage minimizes the potential of side effects, thereby providing an increased margin of safety.

The compounds of the present invention are also useful as standard or reference compounds, for example as a quality standard or control, in tests or assays involving the inhibition of factor Xa. Such compounds may be provided in a commercial kit, for example, for use in pharmaceutical research involving factor Xa. For example, a compound of the present invention could be used as a reference in an assay to compare its known activity to a compound with an unknown activity. This would ensure the experimenter that the assay was being performed properly and provide a basis for comparison, especially if the test compound was a derivative of the reference compound. When developing new assays or protocols, compounds according to the present invention could be used to test their effectiveness.

The compounds of the present invention may also be used in diagnostic assays involving factor Xa. For example, the presence of factor Xa in an unknown sample could be determined by addition of chromogenic substrate S2222 to a series of solutions containing test sample and optionally one of the compounds of the present invention. If production of pNA is observed in the solutions containing test sample, but not in the presence of a compound of the present invention, then one would conclude factor Xa was present.

Dosage and Formulation

The compounds of this invention can be administered in such oral dosage forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. They may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts. They can be administered alone, but generally will be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.

The dosage regimen for the compounds of the present invention will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; the route of administration, the renal and hepatic function of the patient, and the effect desired. A physician or veterinarian can determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the thromboembolic disorder.

By way of general guidance, the daily oral dosage of each active ingredient, when used for the indicated effects, will range between about 0.001 to 1000 mg/kg of body weight, preferably between about 0.01 to 100 mg/kg of body weight per day, and most preferably between about 1.0 to 20 mg/kg/day. Intravenously, the most preferred doses will range from about 1 to about 10 mg/kg/minute during a constant rate infusion. Compounds of this invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four times daily.

Compounds of this invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using transdermal skin patches. When administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.

The compounds are typically administered in admixture with suitable pharmaceutical diluents, excipients, or carriers (collectively referred to herein as pharmaceutical carriers) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.

For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl callulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.

The compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.

Compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues. Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked or amphipathic block copolymers of hydrogels.

Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 1 milligram to about 100 milligrams of active ingredient per dosage unit. In these pharmaceutical compositions the active ingredient will ordinarily be present in an amount of about 0.5-95% by weight based on the total weight of the composition.

Gelatin capsules may contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents. Also used are citric acid and its salts and sodium EDTA. In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field.

Representative useful pharmaceutical dosage-forms for administration of the compounds of this invention can be illustrated as follows:

Capsules

A large number of unit capsules can be prepared by filling standard two-piece hard gelatin capsules each with 100 milligrams of powdered active ingredient, 150 milligrams of lactose, 50 milligrams of cellulose, and 6 milligrams magnesium stearate.

Soft Gelatin Capsules

A mixture of active ingredient in a digestable oil such as soybean oil, cottonseed oil or olive oil may be prepared and injected by means of a positive displacement pump into gelatin to form soft gelatin capsules containing 100 milligrams of the active ingredient. The capsules should be washed and dried.

Tablets

Tablets may be prepared by conventional procedures so that the dosage unit is 100 milligrams of active ingredient, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams of microcrystalline cellulose, 11 milligrams of starch and 98.8 milligrams of lactose. Appropriate coatings may be applied to increase palatability or delay absorption.

Injectable

A parenteral composition suitable for administration by injection may be prepared by stirring 1.5% by weight of active ingredient in 10% by volume propylene glycol and water. The solution should be made isotonic with sodium chloride and sterilized.

Suspension

An aqueous suspension can be prepared for oral administration so that each 5 mL contain 100 mg of finely divided active ingredient, 200 mg of sodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution, U.S.P., and 0.025 mL of vanillin.

Where the compounds of this invention are combined with other anticoagulant agents, for example, a daily dosage may be about 0.1 to 100 milligrams of the compound of Formula I and about 1 to 7.5 milligrams of the second anticoagulant, per kilogram of patient body weight. For a tablet dosage form, the compounds of this invention generally may be present in an amount of about 5 to 10 milligrams per dosage unit, and the second anti-coagulant in an amount of about 1 to 5 milligrams per dosage unit.

Where the compounds of Formula I are administered in combination with an anti-platelet agent, by way of general guidance, typically a daily dosage may be about 0.01 to 25 milligrams of the compound of Formula I and about 50 to 150 milligrams of the anti-platelet agent, preferably about 0.1 to 1 milligrams of the compound of Formula I and about 1 to 3 milligrams of antiplatelet agents, per kilogram of patient body weight.

Where the compounds of Formula I are adminstered in combination with thrombolytic agent, typically a daily dosage may be about 0.1 to 1 milligrams of the compound of Formula I, per kilogram of patient body weight and, in the case of the thrombolytic agents, the usual dosage of the thrombolyic agent when administered alone may be reduced by about 70-80% when administered with a compound of Formula I.

Where two or more of the foregoing second therapeutic agents are administered with the compound of Formula I, generally the amount of each component in a typical daily dosage and typical dosage form may be reduced relative to the usual dosage of the agent when administered alone, in view of the additive or synergistic effect of the therapeutic agents when administered in combination.

Particularly when provided as a single dosage unit, the potential exists for a chemical interaction between the combined active ingredients. For this reason, when the compound of Formula I and a second therapeutic agent are combined in a single dosage unit they are formulated such that although the active ingredients are combined in a single dosage unit, the physical contact between the active ingredients is minimized (that is, reduced). For example, one active ingredient may be enteric coated. By enteric coating one of the active ingredients, it is possible not only to minimize the contact between the combined active ingredients, but also, it is possible to control the release of one of these components in the gastrointestinal tract such that one of these components is not released in the stomach but rather is released in the intestines. One of the active ingredients may also be coated with a material which effects a sustained-release throughout the gastrointestinal tract and also serves to minimize physical contact between the combined active ingredients. Furthermore, the sustained-released component can be additionally enteric coated such that the release of this component occurs only in the intestine. Still another approach would involve the formulation of a combination product in which the one component is coated with a sustained and/or enteric release polymer, and the other component is also coated with a polymer such as a lowviscosity grade of hydroxypropyl methylcellulose (HPMC) or other appropriate materials as known in the art, in order to further separate the active components. The polymer coating serves to form an additional barrier to interaction with the other component.

These as well as other ways of minimizing contact between the components of combination products of the present invention, whether administered in a single dosage form or administered in separate forms but at the same time by the same manner, will be readily apparent to those skilled in the art, once armed with the present disclosure.

Obviously, numerous modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that within the scope of the appended claims, the invention may be practiced otherwise that as specifically described herein. 

What is claimed as new and desired to be secured by Letter Patent of United States is:
 1. A compound of formula I: ##STR265## or a stereoisomer or pharmaceutically acceptable salt thereof, wherein; ring M is pyrazole;J is N or NH; D is selected from CN, C(═NR⁸)NR⁷ R⁹, NHC(═NR⁸)NR⁷ R⁹, NR⁸ C(═NR⁷), C(O)NR⁷ R⁸, and (CR⁸ R⁹)_(t) NR⁷ R⁸, provided that D is substituted meta or para to G on E; E is phenyl substituted with 1 R; R is selected from H, halogen, (CH₂)_(t) OR³, C₁₋₄ alkyl, OCF₃, and CF₃ ; G is absent or is selected from NHCH₂, OCH₂, and SCH₂, provided that when s is 0, then G is attached to a carbon atom on ring M; Z is selected from a C₁₋₄ alkylene, (CH₂)_(r) C(O)(CH₂)_(r), (CH₂)_(r) C(O)NR³ (CH₂)_(r), (CH₂)_(r) NR³ C(O)(CH₂)_(r), (CH₂)_(r) S(O)_(p) (CH₂)_(r), provided that Z does not form a N--N, N--O, N--S, NCH₂ N, NCH₂ O, or NCH₂ S bond with ring M or group A; R^(1a) and R^(1b) are independently absent or selected from --(CH₂)_(r) --R^(1'), NCH₂ R^(1"), OCH₂ R^(1"), SCH₂ R^(1"), N(CH₂)₂ (CH₂)_(t) R^(1'), O(CH₂)₂ (CH₂)_(t) R^(1'), and S(CH₂)₂ (CH₂)_(t) R^(1'), or combined to form a 5-8 membered saturated, partially saturated or unsaturated ring substituted with 0-2 R⁴ and which contains from 0-2 heteroatoms selected from the group consisting of N, O, and S; R^(1') is selected from H, C₁₋₃ alkyl, halo, (CF₂)_(r) CF₃, OR², NR² R^(2a), C(O)R^(2c), OC(O)R², (CF₂)_(r) CO₂ R^(2c), S(O)_(p) R^(2b), NR² (CH₂)_(r) OR², NR² C(O)R^(2b), NR² C(O)NHR^(2b), NR² C(O)₂ R^(2a), OC(O)NR^(2b), C(O)NR² R^(2a), SO₂ NR² R^(2a), NR² SO₂ R^(2b), C₃₋₆ carbocyclic residue substituted with 0-2 R⁴, and 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R⁴ ; R^(1") is selected from H, C(O)R^(2b), C(O)NR² R^(2a), S(O)R^(2b), S(O)₂ R^(2b), and SO₂ NR² R^(2a) ; R², at each occurrence, is selected from H, CF₃, C₁₋₆ alkyl, benzyl, C₃₋₆ carbocyclic residue substituted with 0-2 R^(4b), and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R^(4b) ; R^(2a), at each occurrence, is selected from H, CF₃, C₁₋₆ alkyl, benzyl, C₃₋₆ carbocyclic residue substituted with 0-2 R^(4b), and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R^(4b) ; R^(2b), at each occurrence, is selected from CF₃, C₁₋₄ alkoxy, C₁₋₆ alkyl, benzyl, C₃₋₆ carbocyclic residue substituted with 0-2 R^(4b), and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R^(4b) ; R^(2c), at each occurrence, is selected from CF₃, OH, C₁₋₄ alkoxy, C₁₋₆ alkyl, benzyl, C₃₋₆ carbocyclic residue substituted with 0-2 R_(4b), and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R^(4b) ; alternatively, R² and R^(2a) combine to form a 5 or 6 membered saturated, partially saturated or unsaturated ring substituted with 0-2 R^(4b) which contains from 0-1 additional heteroatoms selected from the group consisting of N, O, and S; R³, at each occurrence, is selected from H, C₁₋₄ alkyl, and phenyl; R^(3a), at each occurrence, is selected from H, C₁₋₄ alkyl, and phenyl; A is selected from:phenyl substituted with 0-2 R⁴, and pyridyl substituted with 0-2 R⁴ ; B is selected from:Y, X--Y, NR² R^(2a), C(═NR²)NR² R^(2a), and NR² C(═NR²)NR² R^(2a) ; X is selected from C₁₋₄ alkylene, --CR² (CR² R^(2b))(CH₂)_(t) --, --C(O)--, --C(═NR)--, --CR² (NR^(1") R²)--, --CR² (OR²)--, --CR² (SR²)--, --C(O)CR² R^(2a) --, --CR² R^(2a) C(O), --S(O)_(p) --, --S(O)_(p) CR² R^(2a) --, --CR² R^(2a) S(O)_(p) --, --C(O)NR² --, --NR² C(O)--, --C(O)NR² CR² R^(2a) --, --NR² C(O)CR² R^(2a) --, --CR² R^(2a) C(O)NR² --, and --CR² R^(2a) NR² C(O)--; Y is selected from:(CH₂)_(r) NR² R^(2a), provided that X--Y do not form a N--N, O--N, or S--N bond, C₃₋₁₀ carbocyclic residue substituted with 0-2 R^(4a), and - 6membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R^(4a) ; R⁴, at each occurrence, is selected from ═O, (CH₂)_(r) OR², halo, C₁₋₄ alkyl, --CN, NO₂, (CH₂)_(r) NR² R^(2a), (CH₂)_(r) C(O)R^(2b), NR² C(O)R^(2b), C(O)NR² R^(2a), NR² C(O)NR² R^(2a), C(═NR²)NR² R^(2a), NHC(═NR²)NR² R^(2a), SO₂ NR² R^(2a), NR² SO₂ NR² R^(2a), NR² SO₂ --C₁₋₄ alkyl, NR² SO₂ R⁵, S(O)_(p) R⁵, (CF₂)_(r) CF₃, NCH₂ R^(1"), OCH₂ R^(1"), SCH₂ R^(1"), N(CH₂)₂ (CH₂)_(t) R^(1'), O(CH₂)₂ (CH₂)_(t) R^(1'), and S(CH₂)₂ (CH₂)_(t) R^(1'), alternatively, one R⁴ is a 5-6 membered aromatic heterocycle containing from 1-4 heteroatoms selected from the group consisting of N, O, and S; R^(4a), at each occurrence, is selected from ═O, (CH₂)_(r) OR², halo, C₁₋₄ alkyl, --CN, NO₂, (CH₂)_(r) NR² R^(2a), (CH₂)_(r) C(O)R^(2b), NR² C(O)R^(2b), C(O)NR² R^(2a), NR² C(O)NR² R^(2a), C(═NR²)NR² R^(2a), NHC(═NR²)NR² R^(2a), SO₂ NR² R^(2a), NR² SO₂ NR² R^(2a), NR² SO₂ --C₁₋₄ alkyl, NR² SO₂ R⁵, S(O)_(p) R⁵, and (CF₂)_(r) CF₃ ; alternatively, one R^(4a) is a 5-6 membered aromatic heterocycle containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-1 R⁵ ; R^(4b), at each occurrence, is selected from ═O, (CH₂)_(r) OR³, halo, C₁₋₄ alkyl, --CN, NO₂, (CH₂)_(r) NR³ R^(3a), (CH₂)_(r) C(O)R³, NR³ C(O)R^(3a), C(O)NR³ R^(3a), NR³ C(O)NR³ R^(3a), C(═NR³)NR³ R^(3a), NH³ C(═NR³)NR³ R^(3a), SO₂ NR³ R^(3a), NR³ SO₂ NR³ R^(3a), NR³ SO₂ --C₁₋₄ alkyl, NR³ SO₂ CF₃, NR³ SO₂ -phenyl, S(O)_(p) CF₃, S(O)_(p) --C₁₋₄ alkyl, S(O)_(p) -phenyl, and (CF₂)_(r) CF₃ ; R⁵, at each occurrence, is selected from CF₃, C₁₋₆ alkyl, phenyl substituted with 0-2 R⁶, and benzyl substituted with 0-2 R⁶ ; R⁶, at each occurrence, is selected from H, OH, (CH₂)_(r) OR², halo, C₁₋₄ alkyl, CN, NO₂, (CH₂)_(r) NR² R^(2a), (CH₂)_(r) C(O)R^(2b), NR² C(O)R^(2b), NR² C(O)NR² R^(2a), C(═NH)NH₂, NHC(═NH)NH₂, SO₂ NR² R^(2a), NR² SO₂ NR² R^(2a), and NR² SO₂ C₁₋₄ alkyl; R⁷, at each occurrence, is selected from H, OH, C₁₋₆ alkyl, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxy, C₁₋₄ alkoxycarbonyl, (CH₂)_(n) -phenyl, C₆₋₁₀ aryloxy, C₆₋₁₀ aryloxycarbonyl, C₆₋₁₀ arylmethylcarbonyl, C₁₋₄ alkylcarbonyloxy C₁₋₄ alkoxycarbonyl, C₆₋₁₀ arylcarbonyloxy C₁₋₄ alkoxycarbonyl, C₁₋₆ alkylaminocarbonyl, phenylaminocarbonyl, and phenyl C₁₋₄ alkoxycarbonyl; R⁸, at each occurrence, is selected from H, C₁₋₆ alkyl and (CH₂)_(n) -phenyl; alternatively, R⁷ and R⁸ combine to form a 5 or 6 membered saturated, ring which contains from 0-1 additional heteroatoms selected from the group consisting of N, O, and S; R⁹, at each occurrence, is selected from H, C₁₋₆ alkyl and (CH₂)_(n) -phenyl; n, at each occurrence, is selected from 0, 1, 2, and 3; p, at each occurrence, is selected from 0, 1, and 2; r, at each occurrence, is selected from 0, 1, 2, and 3; s, at each occurrence, is selected from 0, 1, and 2; and, t, at each occurrence, is selected from 0 and 1; provided that D--E--G--(CH₂)_(s) -- and --Z--A--B are not both benzamidines and that --Z--A--B does not form a substituted or unsubstituted biphenylmethylene group.
 2. A compound of formulae Ib: ##STR266## wherein, groups D--E-- and --Z--A--B are attached to adjacent atoms on the ring;J is N or NH; D is selected from CN, C(═NR⁸)NR⁷ R⁹, NHC(═NR⁸)NR⁷ R⁹, NR⁸ C(═NR⁷), C(O)NR⁷ R⁸, and (CR⁸ R⁹)_(t) NR⁷ R⁸, provided that D is substituted meta or para to G on E; E is phenyl substituted with 1 R; R is selected from H, halogen, (CH₂)_(t) OR³, C₁₋₄ alkyl, OCF₃, and CF₃ ; G is absent or is selected from NHCH₂, OCH₂, and SCH₂, provided that when s is 0, then G is attached to a carbon atom on ring M; Z is selected from a C(O), CH₂ C(O), C(O)CH₂, NHC(O), C(O)NH, CH₂ S(O)₂, and S(O)₂ (CH₂), provided that Z does not form a N--N or NCH₂ N bond with ring M or group A; R^(1a) and R^(1b) are independently absent or selected from --(CH₂)_(r) --R^(1'), NCH₂ R^(1"), OCH₂ R^(1"), SCH₂ R^(1"), N(CH₂)₂ (CH₂)_(t) R^(1'), O(CH₂)₂ (CH₂)_(t) R^(1'), and S(CH₂)₂ (CH₂)_(t) R^(1'), or combined to form a 5-8 membered saturated, partially saturated or unsaturated ring substituted with 0-2 R⁴ and which contains from 0-2 heteroatoms selected from the group consisting of N, O, and S; R^(1') is selected from H, C₁₋₃ alkyl, halo, (CF₂)_(r) CF₃, OR², NR² R^(2a), C(O)R^(2c), OC(O)R², (CF₂)_(r) CO₂ R^(2c), S(O)_(p) R^(2b), NR² (CH₂)_(r) OR², NR² C(O)R^(2b), NR² C(O)NHR^(2b), NR² C(O)₂ R^(2a), OC(O)NR^(2b), C(O)NR² R^(2a), SO₂ NR² R^(2a), NR² SO₂ R^(2b), C₃₋₆ carbocyclic residue substituted with 0-2 R⁴, and 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R⁴ ; R^(1") is selected from H, C(O)R^(2b), C(O)NR² R^(2a), S(O)R^(2b), S(O)₂ R^(2b), and SO₂ NR² R^(2a) ; R², at each occurrence, is selected from H, CF₃, C₁₋₆ alkyl, benzyl, C₃₋₆ carbocyclic residue substituted with 0-2 R^(4b), and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R^(4b) ; R^(2a), at each occurrence, is selected from H, CF₃, C₁₋₆ alkyl, benzyl, C₃₋₆ carbocyclic residue substituted with 0-2 R^(4b), and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R^(4b) ; R^(2b), at each occurrence, is selected from CF₃, C₁₋₄ alkoxy, C₁₋₆ alkyl, benzyl, C₃₋₆ carbocyclic residue substituted with 0-2 R_(4b), and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R^(4b) ; R^(2c), at each occurrence, is selected from CF₃, OH, C₁₋₄ alkoxy, C₁₋₆ alkyl, benzyl, C₃₋₆ carbocyclic residue substituted with 0-2 R^(4b), and 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R^(4b) ; alternatively, R² and R^(2a) combine to form a 5 or 6 membered saturated, partially saturated or unsaturated ring substituted with 0-2 R^(4b) which contains from 0-1 additional heteroatoms selected from the group consisting of N, O, and S; R³, at each occurrence, is selected from H, C₁₋₄ alkyl, and phenyl; R^(3a), at each occurrence, is selected from H, C₁₋₄ alkyl, and phenyl; A is selected from:phenyl substituted with 0-2 R⁴, and pyridyl substituted with 0-2 R⁴ ; B is selected from: Y, X--Y, NR² R^(2a), C(═NR²)NR² R^(2a), and NR² C(═NR²)NR² R^(2a) ; X is selected from C₁₋₄ alkylene, --C(O)--, --C(═NR)--, --CR² (NR² R^(2a))--, --C(O)CR² R^(2a) --, --CR² R^(2a) C(O), --C(O)NR² --, --NR² C(O)--, --C(O)NR² CR² R^(2a) --, --NR² C(O)CR² R^(2a) --, --CR² R^(2a) C(O)NR² --, and --CR² R^(2a) NR² C(O)--; Y is NR² R^(2a), provided that X--Y do not form a N--N or O--N bond; alternatively, Y is selected from one of the followingcarbocyclic and heterocyclic systems which are substituted with 0-2 R^(4a) ; cyclopropyl, cyclopentyl, cyclohexyl, phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, isoxazolinyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, and 1,3,4-triazolyl; R⁴, at each occurrence, is selected from ═O, (CH₂)_(r) OR², halo, C₁₋₄ alkyl, --CN, NO₂, (CH₂)_(r) NR² R^(2a), (CH₂)_(r) C(O)R^(2b), NR² C(O)R^(2b), C(O)NR² R^(2a), NR² C(O)NR² R^(2a), C(═NR²)NR² R^(2a), NHC(═NR²)NR² R^(2a), SO₂ NR² R^(2a), NR² SO₂ NR² R^(2a), NR² SO₂ --C₁₋₄ alkyl, NR² SO₂ R⁵, S(O)_(p) R⁵, (CF₂)_(r) CF₃, NCH₂ R^(1"), OCH₂ R^(1"), SCH₂ R^(1"), N(CH₂)₂ (CH₂)_(t) R^(1'), O(CH₂)₂ (CH₂)_(t) R^(1'), and S(CH₂)₂ (CH₂)_(t) R^(1'), alternatively, one R⁴ is a 5-6 membered aromatic heterocycle containing from 1-4 heteroatoms selected from the group consisting of N, O, and S; R^(4a), at each occurrence, is selected from ═O, (CH₂)_(r) OR², halo, C₁₋₄ alkyl, --CN, NO₂, (CH₂)_(r) NR² R^(2a), (CH₂)_(r) C(O)R^(2b), NR² C(O)R^(2b), C(O)NR² R^(2a), NR² C(O)NR² R^(2a), C(═NR²)NR² R^(2a), NHC(═NR²)NR² R^(2a), SO₂ NR² R^(2a), NR² SO₂ NR² R^(2a), NR² SO₂ --C₁₋₄ alkyl, NR² SO₂ R⁵, S(O)_(p) R⁵, and (CF₂)_(r) CF₃ ; alternatively, one R^(4a) is a 5-6 membered aromatic heterocycle containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-1 R⁵ ; R^(4b), at each occurrence, is selected from ═O, (CH₂)_(r) OR³, halo, C₁₋₄ alkyl, --CN, NO₂, (CH₂)_(r) NR³ R^(3a), (CH₂)_(r) C(O)R³, NR³ C(O)R^(3a), C(O)NR³ R^(3a), NR³ C(O)NR³ R^(3a), C(═NR³)NR³ R^(3a), NH³ C(═NR³)NR³ R^(3a), SO₂ NR³ R^(3a), NR³ SO₂ NR³ R^(3a), NR³ SO₂ --C₁₋₄ alkyl, NR³ SO₂ CF₃, NR³ SO₂ -phenyl, S(O)_(p) CF₃, S(O)_(p) --C₁₋₄ alkyl, S(O)_(p) -phenyl, and (CF₂)_(r) CF₃ ; R⁵, at each occurrence, is selected from CF₃, C₁₋₆ alkyl, phenyl substituted with 0-2 R⁶, and benzyl substituted with 0-2 R⁶ ; R⁶, at each occurrence, is selected from H, OH, (CH₂)_(r) OR², halo, C₁₋₄ alkyl, CN, NO₂, (CH₂)_(r) NR² R^(2a), (CH₂)_(r) C(O)R^(2b), NR² C(O)R^(2b), NR² C(O)NR² R^(2a), C(═NH)NH₂, NHC(═NH)NH₂, SO₂ NR² R^(2a), NR² SO₂ NR² R^(2a), and NR² SO₂ C₁₋₄ alkyl; R⁷, at each occurrence, is selected from H, OH, C₁₋₆ alkyl, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxy, C₁₋₄ alkoxycarbonyl, (CH₂)_(n) -phenyl, C₆₋₁₀ aryloxy, C₆₋₁₀ aryloxcarbonyl, C₆₋₁₀ arylmethylcarbonyl, C₁₋₄ alkylcarbonyloxy C₁₋₄ alkoxycarbonyl, C₆₋₁₀ arylcarbonyloxy C₁₋₄ alkoxycarbonyl, C₁₋₆ alkylaminocarbonyl, phenylaminocarbonyl, and phenyl C₁₋₄ alkoxycarbonyl; R⁸, at each occurrence, is selected from H, C₁₋₆ alkyl and (CH₂)_(n) -phenyl; alternatively, R⁷ and R⁸ combine to form a 5 or 6 membered saturated, ring which contains from 0-1 additional heteroatoms selected from the group consisting of N, O, and S; R⁹, at each occurrence, is selected from H, C₁₋₆ alkyl and (CH₂)_(n) -phenyl; n, at each occurrence, is selected from 0, 1, 2, and 3; p, at each occurrence, is selected from 0, 1, and 2; r, at each occurrence, is selected from 0, 1, 2, and 3; s, at each occurrence, is selected from 0, 1, and 2; and, t, at each occurrence, is selected from 0 and 1; provided that D--E--G--(CH₂)_(s) -- and --Z--A--B are not both benzamidines and that --Z--A--B does not form a substituted or unsubstituted biphenylmethylene group.
 3. A compound according to claim 2, the compound is of formulae IIa: ##STR267## wherein; Z is selected from a C(O), CH₂ C(O), C(O)CH₂, NHC(O), C(O)NH, CH₂ S(O)₂, and S(O)₂ (CH₂), provided that Z does not form a N--N or NCH₂ N bond with ring M or group A.
 4. A compound according to claim 3, wherein;D is selected from NH₂, C(O)NH₂, C(═NH)NH₂, CH₂ NH₂, CH₂ NHCH₃, CH(CH₃)NH₂, and C(CH₃)₂ NH₂, provided that D is substituted meta or para to ring M on E; and, R is selected from H, OCH₃, Cl, and F.
 5. A compound according to claim 4, wherein;D--E is selected from 3-aminophenyl, 3-amidinophenyl, 3-aminomethylphenyl, 3-aminocarbonylphenyl, 3-(methylaminomethyl)phenyl, 3-(1-aminoethyl)phenyl, 3-(2-amino-2-propyl)phenyl, 4-chloro-3-aminophenyl, 4-chloro-3-amidinophenyl, 4-chloro-3-aminomethylphenyl, 4-chloro-3-(methylaminomethyl)phenyl, 4-fluoro-3-aminophenyl, 4-fluoro-3-amidinophenyl, 4-fluoro-3-aminomethylphenyl, and 4-fluoro-3-(methylaminomethyl)phenyl.
 6. A compound according to claim 3, wherein;Z is C(O)CH₂ and CONH, provided that Z does not form a N--N bond with group A; B is selected from X--Y, phenyl, pyrrolidino, morpholino, 1,2,3-triazolyl, and imidazolyl, and is substituted with 0-1 R^(4a) ; R⁴, at each occurrence, is selected from OH, (CH₂)_(r) OR², halo, C₁₋₄ alkyl, (CH₂)_(r) NR² R^(2a), and (CF₂)_(r) CF₃ ; R^(4a) is selected from C₁₋₄ alkyl, CF₃, S(O)_(p) R⁵, SO₂ NR² R^(2a), and 1-CF₃ -tetrazol-2-yl; R⁵, at each occurrence, is selected from CF₃, C₁₋₆ alkyl, phenyl, and benzyl; X is CH₂ or C(O); and, Y is selected from pyrrolidino and morpholino.
 7. A compound according to claim 6, wherein;A is selected from the group: phenyl, 2-pyridyl, 3-pyridyl, 2-Cl-phenyl, 3-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 2-methylphenyl, 2-aminophenyl, and 2-methoxyphenyl; and, B is selected from the group: 2-CF₃ -phenyl, 2-(aminosulfonyl)phenyl, 2-(methylaminosulfonyl)phenyl, 2-(dimethylaminosulfonyl)phenyl, 1-pyrrolidinocarbonyl, 2-(methylsulfonyl)phenyl, 4-morpholino, 2-(1'-CF₃ -tetrazol-2-yl)phenyl, 4-morpholinocarbonyl, 2-methyl-1-imidazolyl, 5-methyl-1-imidazolyl, 2-methylsulfonyl-1-imidazolyl and, 5-methyl-1,2,3-triazolyl.
 8. A compound according to claim 3, wherein;D is selected from NH₂, C(O)NH₂, C(═NH)NH₂, CH₂ NH₂, CH₂ NHCH₃, CH(CH₃)NH₂, and C(CH₃)₂ NH₂, provided that D is substituted meta or para to ring M on E; and, R is selected from H, OCH₃, Cl, and F; Z is C(O)CH₂ and CONH, provided that Z does not form a N--N bond with group A; B is selected from X--Y, phenyl, pyrrolidino, morpholino, 1,2,3-triazolyl, and imidazolyl, and is substituted with 0-1 R^(4a) ; R⁴, at each occurrence, is selected from OH, (CH₂)_(r) OR², halo, C₁₋₄ alkyl, (CH₂)_(r) NR² R^(2a), and (CF₂)_(r) CF₃ ; R^(4a) is selected from C₁₋₄ alkyl, CF₃, S(O)_(p) R⁵, SO₂ NR² R^(2a), and 1-CF₃ -tetrazol-2-yl; R⁵, at each occurrence, is selected from CF₃, C₁₋₆ alkyl, phenyl, and benzyl; X is CH₂ or C(O); and, Y is selected from pyrrolidino and morpholino.
 9. A compound according to claim 8, wherein;D--E is selected from 3-aminophenyl, 3-amidinophenyl, 3-aminomethylphenyl, 3-aminocarbonylphenyl, 3-(methylaminomethyl)phenyl, 3-(1-aminoethyl)phenyl, 3-(2-amino-2-propyl)phenyl, 4-chloro-3-aminophenyl, 4-chloro-3-amidinophenyl, 4-chloro-3-aminomethylphenyl, 4-chloro-3-(methylaminomethyl)phenyl, 4-fluoro-3-aminophenyl, 4-fluoro-3-amidinophenyl, 4-fluoro-3-aminomethylphenyl, and 4-fluoro-3-(methylaminomethyl)phenyl; A is selected from the group: phenyl, 2-pyridyl, 3-pyridyl, 2-Cl-phenyl, 3-Cl-phenyl, 2-F-phenyl, 3-F-phenyl, 2-methylphenyl, 2-aminophenyl, and 2-methoxyphenyl; and, B is selected from the group: 2-CF₃ -phenyl, 2-(aminosulfonyl)phenyl, 2-(methylaminosulfonyl)phenyl, 2-(dimethylaminosulfonyl)phenyl, 1-pyrrolidinocarbonyl, 2-(methylsulfonyl)phenyl, 4-morpholino, 2-(1'-CF₃ -tetrazol-2-yl)phenyl, 4-morpholinocarbonyl, 2-methyl-1-imidazolyl, 5-methyl-1-imidazolyl, 2-methylsulfonyl-1-imidazolyl and, 5-methyl-1,2,3-triazolyl.
 10. A compound according to claim 3, wherein;D is selected from C(═NR⁸)NR⁷ R⁹, C(O)NR⁷ R⁸, NR⁷ R⁸, and CH₂ NR⁷ R⁸, provided that D is substituted meta or para to ring M on E; R is selected from H, Cl, F, OR³, CH₃, CH₂ CH₃, OCF₃, and CF₃ ; Z is selected from C(O), CH₂ C(O), C(O)CH₂, NHC(O), and C(O)NH, provided that Z does not form a N--N bond with ring M or group A; R^(1a) and R^(1b) are independently absent or selected from --(CH₂)_(r) --R^(1'), NCH₂ R^(1"), OCH₂ R^(1"), SCH₂ R^(1"), N(CH₂)₂ (CH₂)_(t) R^(1'), O(CH₂)₂ (CH₂)_(t) R^(1'), and S(CH₂)₂ (CH₂)_(t) R^(1'), or combined to form a 5-8 membered saturated, partially saturated or unsaturated ring substituted with 0-2 R⁴ and which contains from 0-2 heteroatoms selected from the group consisting of N, O, and S; R^(1'), at each occurrence, is selected from H, C₁₋₃ alkyl, halo, (CF₂)_(r) CF₃, OR², NR² R^(2a), C(O)R^(2c), (CF₂)_(r) CO₂ R^(2c), S(O)_(p) R^(2b), NR² (CH₂)_(r) OR², NR² C(O)R^(2b), NR² C(O)₂ R^(2b), C(O)NR² R^(2a), SO₂ NR² R^(2a), and NR² SO₂ R^(2b) ; B is selected from: Y, X--Y, NR² R^(2a), C(═NR²)NR² R^(2a), and NR² C(═NR²)NR² R^(2a) ; X is selected from CH₂, --C(O)--, --C(═NR)--, --CH(NR² R^(2a))--, --C(O)NR² --, and --NR² C(O)--; Y is NR² R^(2a), provided that X--Y do not form a N--N or O--N bond; alternatively, Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R^(4a) ;phenyl, piperidinyl, piperazinyl, pyridyl, pyrimidyl, furanyl, morpholinyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, isoxazolyl, isoxazolinyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, and 1,3,4-triazolyl; R⁴, at each occurrence, is selected from ═O, OH, Cl, F, C₁₋₄ alkyl, (CH₂)_(r) NR² R^(2a), (CH₂)_(r) C(O)R^(2b), NR² C(O)R_(2b), C(O)NR² R^(2a), C(═NH)NH₂, NHC(═NH)NH₂, SO₂ NR² R^(2a), NR² SO₂ --C₁₋₄ alkyl, NR² SO₂ R⁵, S(O)_(p) R⁵, and (CF₂)_(r) CF₃ ; R^(4a), at each occurrence, is selected from ═O, OH, Cl, F, C₁₋₄ alkyl, (CH₂)_(r) NR² R^(2a), (CH₂)_(r) C(O)R^(2b), NR² C(O)R^(2b), C(O)NR² R^(2a), C(═NH)NH₂, NHC(═NH)NH₂, SO₂ NR² R^(2a), NR² SO₂ --C₁₋₄ alkyl, NR² SO₂ R⁵, S(O)_(p) R⁵, (CF₂)_(r) CF₃, and 1-CF₃ -tetrazol-2-yl; R⁵, at each occurrence, is selected from CF₃, C₁₋₆ alkyl, phenyl substituted with 0-2 R⁶, and benzyl substituted with 0-2 R⁶ ; R⁶, at each occurrence, is selected from H, OH, OR², Cl, F, CH₃, CN, NO₂, (CH₂)_(r) NR² R^(2a), (CH₂)_(r) C(O)R^(2b), NR² C(O)R^(2b), C(═NH)NH₂, NHC(═NH)NH₂, and SO₂ NR² R^(2a) ; R⁷, at each occurrence, is selected from H, OH, C₁₋₆ alkyl, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxy, C₁₋₄ alkoxycarbonyl, benzyl, C₆₋₁₀ aryloxy, C₆₋₁₀ aryloxycarbonyl, C₆₋₁₀ arylmethylcarbonyl, C₁₋₄ alkylcarbonyloxy C₁₋₄ alkoxycarbonyl, C₆₋₁₀ arylcarbonyloxy C₁₋₄ alkoxycarbonyl, C₁₋₆ alkylaminocarbonyl, phenylaminocarbonyl, and phenyl C₁₋₄ alkoxycarbonyl; R⁸, at each occurrence, is selected from H, C₁₋₆ alkyl and benzyl; and alternatively, R⁷ and R⁸ combine to form a morpholino group; and, R⁹, at each occurrence, is selected from H, C₁₋₆ alkyl and benzyl.
 11. A compound according to claim 10, wherein;R is selected from H, Cl, F, OCH₃, CH₃, OCF₃, and CF₃ ; Z is selected from a C(O)CH₂ and C(O)NH, provided that Z does not form a N--N bond with group A; R^(1a) is absent or is selected from H, CH₃, CH₂ CH₃, Cl, F, CF₃, OCH₃, NR² R^(2a), S(O)_(p) R^(2b), CH₂ S(O)_(p) R^(2b), C(O)R^(2c), CH₂ C(O)R^(2c), C(O)NR² R^(2a), and SO₂ NR² R^(2a) ; R^(1b) is absent or is selected from H, CH₃, CH₂ CH₃, Cl, F, CF₃, OCH₃, NR² R^(2a), S(O)_(p) R^(2b), CH₂ S(O)_(p) R^(2b), C(O)R^(2c), CH₂ C(O)R^(2c), C(O)NR² R^(2a), and SO₂ NR² R^(2a) ; B is selected from: Y and X--Y; R², at each occurrence, is selected from H, CF₃, CH₃, benzyl, and phenyl; R^(2a), at each occurrence, is selected from H, CF₃, CH₃, benzyl, and phenyl; R^(2b), at each occurrence, is selected from CF₃, OCH₃, CH₃, benzyl, and phenyl; R^(2c), at each occurrence, is selected from CF₃, OH, OCH₃, CH₃, benzyl, and phenyl; alternatively, R² and R^(2a) combine to form a 5 or 6 membered saturated, partially unsaturated, or unsaturated ring which contains from 0-1 additional heteroatoms selected from the group consisting of N, O, and S; R³, at each occurrence, is selected from H, CH₃, CH₂ CH₃, and phenyl; R^(3a), at each occurrence, is selected from H, CH₃, CH₂ CH₃, and phenyl; R⁴, at each occurrence, is selected from OH, Cl, F, CH₃, CH₂ CH₃, NR² R^(2a), CH₂ NR² R^(2a), C(O)R^(2b), NR² C(O)R^(2b), C(O)NR² R^(2a), and CF₃ ; R^(4a), at each occurrence, is selected from OH, Cl, F, CH₃, CH₂ CH₃, NR² R^(2a), CH₂ NR² R^(2a), C(O)R^(2b), C(O)NR² R^(2a), SO₂ NR² R^(2a), S(O)_(p) R⁵, CF₃, and 1-CF₃ -tetrazol-2-yl; R⁵, at each occurrence, is selected from CF₃, C₁₋₆ alkyl, phenyl substituted with 0-2 R⁶, and benzyl substituted with 1 R⁶ ; R⁶, at each occurrence, is selected from H, OH, OCH₃, Cl, F, CH₃, CN, NO₂, NR² R^(2a), CH₂ NR² R^(2a), and SO₂ NR² R^(2a) ; R⁷, at each occurrence, is selected from H, OH, C₁₋₃ alkyl, C₁₋₃ alkylcarbonyl, C₁₋₃ alkoxy, C₁₋₄ alkoxycarbonyl, benzyl, phenoxy, phenoxycarbonyl, benzylcarbonyl, C₁₋₄ alkylcarbonyloxy C₁₋₄ alkoxycarbonyl, phenylcarbonyloxy C₁₋₄ alkoxycarbonyl, C₁₋₆ alkylaminocarbonyl, phenylaminocarbonyl, and phenyl C₁₋₄ alkoxycarbonyl; R⁸, at each occurrence, is selected from H, CH₃, and benzyl; and, alternatively, R⁷ and R⁸ combine to form a morpholino group; R⁹, at each occurrence, is selected from H, CH₃, and benzyl.
 12. A compound according to claim 11, wherein;X is --C(O)--; Y is NR² R^(2a), provided that X--Y do not form a O--N bond; alternatively, Y is selected from one of the following carbocyclic and heterocyclic systems which are substituted with 0-2 R^(4a) ; phenyl, piperazinyl, pyridyl, pyrimidyl, morpholinyl, pyrrolidinyl, imidazolyl, and 1,2,3-triazolyl; R², at each occurrence, is selected from H, CF₃, CH₃, benzyl, and phenyl; R^(2a), at each occurrence, is selected from H, CF₃, CH₃, benzyl, and phenyl; R^(2b), at each occurrence, is selected from CF₃, OCH₃, CH₃, benzyl, and phenyl; R^(2c), at each occurrence, is selected from CF₃, OH, OCH₃, CH₃, benzyl, and phenyl; alternatively, R² and R^(2a) combine to form a ring system selected from pyrrolidinyl, piperazinyl and morpholino; R⁴, at each occurrence, is selected from Cl, F, CH₃, NR² R^(2a), and CF₃ ; R^(4a), at each occurrence, is selected from Cl, F, CH₃, SO₂ NR² R^(2a), S(O)_(p) R⁵, and CF₃ ; and, R⁵, at each occurrence, is selected from CF₃ and CH₃.
 13. A compound according to claim 1, wherein the compound is selected from the group:1-(3-amidinophenyl)-3-methyl-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole; 1-(3-amidinophenyl)-3-methyl-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)carbonylamino]pyrazole; 1-(3-amidinophenyl)-3-methyl-5-((2'-(5"-CF₃ -tetrazolyl)-[1,1']-biphen-4-yl)aminocarbonyl)pyrazole; 1-(3-amidinophenyl)-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-4-chloro-3-methyl-pyrazole; 1-(3-amidinophenyl)-5-((2'-t-butylaminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl)-3-trifluoromethyl-pyrazole; 1-(3-amidinophenyl)-4-methoxy-5-((2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl)-3-trifluoromethyl-pyrazole; 1-(3-amidinophenyl)-3-methyl-5-(4'-(imidazol-1-ylphenyl)aminocarbonyl)pyrazole; 1-(3-amidinophenyl)-3-methyl-5-[(4'-(2"-sulfonylmethyl)phenoxyphenyl)aminocarbonyl]pyrazole; 1-(3-amidinophenyl)-3-methyl-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)methylcarbonyl]pyrazole; 1-(3-amidinophenyl)-3-methyl-2-[[5-(2'-aminosulfonylphenyl-1-yl)pyridin-2-yl]-aminocarbonyl]pyrazole; 1-(3-amidinophenyl)-3-methyl-5-[(2'-aminosulfonyl-2-chloro-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole; 1-(3-amidinophenyl)-3-methyl-5-[(2'-aminosulfonyl-2-fluoro-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole; 1-(3-amidinophenyl)-3-methyl-5-[(2'-aminosulfonyl-4'-fluoro-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole; 1-(3-amidinophenyl)-3-methyl-5-[(2'-trifluoromethyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole; 1-(3-amidinophenyl)-3-methyl-5-[(3-chloro-2'-trifluoromethyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole; 1-(3-amidinophenyl)-3-methyl-5-[(3-fluoro-2'-trifluoromethyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole; 1-(3-amidinophenyl)-3-methyl-2-[[5-(2'-trifluoromethylphenyl-1-yl)pyridin-2-yl]-aminocarbonyl]pyrazole; 1-(3-amidinophenyl)-3-methyl-5-[(2'-fluoro-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole; 1-(3-amidinophenyl)-3-methyl-5-[(3-chloro-2'-fluoro-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole; 1-(3-amidinophenyl)-3-methyl-5-[(2'-methylsulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole; 1-(3-amidinophenyl)-3-methyl-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)(N'-methyl)aminocarbonyl]pyrazole; 1-(3-amidinophenyl)-3-n-butyl-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole; 1-(3-amidinophenyl)-3-n-butyl-5-[((2'-aminosulfonylphenyl-1-yl)pyridin-2-yl)-aminocarbonyl]pyrazole; 1-(3-amidinophenyl)-3-n-butyl-5-[((2'-trifluoromethylphenyl-1-yl)pyridin-2-yl)-aminocarbonyl]pyrazole; 1-(3-amidinophenyl)-5-[(2'-methylsulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-trifluoromethyl-pyrazole; 1-(3-amidinophenyl)-5-[(2'-trifluoromethyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-trifluoromethyl-pyrazole; 1-(3-amidinophenyl)-4-methoxy-5-((2'-trifluoromethyl-[1,1']-biphen-4-yl)aminocarbonyl)-3-trifluoromethyl-pyrazole; 1-(3-amidinophenyl)-3-methyl-5-[(4-trifluoromethylphenyl)aminocarbonyl]pyrazole; 3-methyl-1-(3-amidinophenyl)-5-((4'-(4"-chlorophenyl)thiazol-2'-yl)aminocarbonyl)pyrazole; 1-(3-amidino)phenyl-3-methyl-5-[(2'-trifluoromethylsulfide-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole; 1-(3-amidino)phenyl-3-methyl-5-[(2'-trifluoromethylsulfoxide-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole; 1-(3-amidino)phenyl-3-methyl-5-[(2'-trifluoromethylsulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole; 1-(3-amidino)phenyl-3-methyl-5-[(4'-benzylsulfonylpiperidyl)aminocarbonyl]pyrazole; 1-(3-amidinophenyl)-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)-N-methylaminocarbonyl]-3-methyl-pyrazole; 1-(3-amidinophenyl)-5-[(4'-fluoro-[1,1']-biphen-4-yl)aminocarbonyl]-3-methyl-pyrazole; 1-(3-amidinophenyl)-5-[[5(2'-aminosulfonylphenyl)pyridin-2-yl]aminocarbonyl]-3-methyl-pyrazole; 1-(3-cyanophenyl)-5-[[5-(2'-aminosulfonylphenyl)pyridin-2-yl]aminocarbonyl]-3-methyl-pyrazole; 1-(3-amidinophenyl)-5-[(2'-trifluoromethyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-methyl-pyrazole; 1-(3-aminocarbonylphenyl)-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-methyl-pyrazole; and, 1-(3-amidinophenyl)-5-[(2'-aminosulfonyl-3-chloro-[1,1']-biphen-4-yl)aminocarbonyl]-3-methyl-pyrazole;or a pharmaceutically acceptable salt thereof.
 14. A compound according to claim 1, wherein the compound is selected from the group:1-(3-amidinophenyl)-5-[(2'-trifluoromethyl-3-chloro-[1,1']-biphen-4-yl)aminocarbonyl]-3-methylpyrazole; 1-(3-amidinophenyl)-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-n-butylpyrazole; 1-(3-amidinophenyl)-5-[(2'-trifluoromethyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-n-butylpyrazole; 1-(3-amidinophenyl)-5-[[5-(2'-aminosulfonylphenyl)pyridin-2-yl]aminocarbonyl]-3-n-butylpyrazole; 1-(3-amidinophenyl)-5-[(2'-trifluoromethyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-trifluoromethyl-4-methoxypyrazole; 1-(3-amidinophenyl)-5-[(2'-trifluoromethyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-trifluoromethyl-pyrazole; 1-(3-amidinophenyl)-5-[(2'-sulfonylmethyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-trifluoromethyl-pyrazole; 1-(3-amidinophenyl)-5-[(2'-aminosulfonyl-3-bromo-[1,1']-biphen-4-yl)aminocarbonyl]-3-methyl-pyrazole; 1-(3-aminocarbonylphenyl)-5-[(2'-aminosulfonyl-3-bromo-[1,1']-biphen-4-yl)aminocarbonyl]-3-methyl-pyrazole; 1-(3-amidinophenyl)-3-methyl-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)methylcarbonyl]pyrazole; 1-(3-aminocarbonylphenyl)-5-[5-[(2'-aminosulfonylphen-1-yl)pyridin-2-yl]aminocarbonyl]-3-methyl-pyrazole; 1-(3-cyanophenyl)-5-[(4'-(imidazol-1-yl)phenyl)aminocarbonyl]-3-trifluoromethyl-pyrazole; 1-(3-amidinophenyl)-5-[(4'-(morpholin-1-yl)phenyl)-aminocarbonyl]-3-trifluoromethyl-pyrazole; 1-(3-aminocarbonylphenyl)-5-[(4'-(morpholin-1-yl)phenyl)aminocarbonyl]-3-trifluoromethyl-pyrazole; 1-(3-amidinophenyl)-5-[[5-(2'-aminosulfonylphenyl)pyridin-2-yl]aminocarbonyl]-3-trifluoromethyl-pyrazole; 1-(3-aminocarbonylphenyl)-5-[[5-(2'-aminosulfonylphenyl)pyridin-2-yl]aminocarbonyl]-3-trifluoromethyl-pyrazole; 1-(3-amidinophenyl)-5-[(4'-(3-methyltetrazol-1-yl)phenyl)aminocarbonyl]-3-trifluoromethyl-pyrazole; 1-(3-amidinophenyl)-5-(2'-napthylaminosulfonyl)-3-methyl-pyrazole; 1-(3-amidinophenyl)-5-[(4-bromophenyl)aminosulfonyl]-3-methyl-pyrazole; 1-(3-aminomethylphenyl)-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-methyl-pyrazole; 1-(3-aminomethylphenyl)-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-trifluoromethyl-pyrazole; 1-(3-amidinophenyl)-3-methyl-5-[((2'-trifluoromethylphenyl)pyrid-2-yl)aminocarbonyl]pyrazole; 1-(3-amidinophenyl)-3-methyl-5-[(2'-fluoro-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole; 1-(3-amidinophenyl)-3-methyl-5-[3-chloro-(2'-fluoro-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole; 1-(3-amidinophenyl)-3-methyl-5-[(3-fluoro-2'-fluoro-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole; 1-(3-amidinophenyl)-3-methyl-5-[(3-fluoro-2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole; 1-(3-amidinophenyl)-3-methyl-5-[[5-(2'-fluorophen-1-yl)pyrid-2-yl]aminocarbonyl]pyrazole; 1-(3-amidinophenyl)-3-methyl-5-[(4-(pyrid-3'-yl)phen-1-yl)aminocarbonyl]pyrazole; 1-(3-amidinophenyl)-3-methyl-5-[[2-(2'-pyridyl)ethyl]aminocarbonyl]pyrazole 1-(3-amidinophenyl)-3-methyl-5-[(3-phenylpropyl)aminocarbonyl]pyrazole; 1-(3-amidinophenyl)-3-methyl-5-[4-(pyrid-2'-yl)phen-1-ylaminocarbonyl]pyrazole; 1-(3-amidinophenyl)-3-methyl-5-[(4-(isopropyloxy)phenyl)aminocarbonyl]pyrazole; 1-(3-amidinophenyl)-3-methyl-5-[(4-(piperidinosulfonyl)phenyl)aminocarbonyl]pyrazole; 1-(3-amidinophenyl)-3-methyl-5-[(4-(piperidinocarbonyl)phenyl)aminocarbonyl]pyrazole; 1-(3-amidino-4-fluorophenyl)-3-methyl-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole; 1-(3-aminocarbonyl-4-fluorophenyl)-3-methyl-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole; 1-methyl-3-(3-amidino)phenyl-4-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole; and, 1-(3-amidinophenyl)-3-methyl-5-[[4-(pyrazol-4'-yl)phen-1-yl]aminocarbonyl]pyrazole;or a pharmaceutically acceptable salt thereof.
 15. A compound according to claim 1, wherein the compound is selected from the group:1-(3-amidinophenyl)-3-methyl-5-([5-(2'-methylsulfonylphenyl)pyrid-2-yl]aminocarbonyl)pyrazole; 1-(3-(N-aminoamidino)phenyl)-3-methyl-5-[(2'-tert-butylaminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole; 1-(3-(N-aminoamidino)phenyl)-3-methyl-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole; 1-(3-(N-methyl-N-hydroxyamidino)phenyl)-3-methyl-5-[(4'-t-butylaminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole; 1-(3-(N-methylamidino)phenyl)-3-methyl-5-[(2'-tert-butylaminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole; 1-(3-(N-methylamidino)phenyl)-3-methyl-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole; 1-[(3-amidinophenyl)methyl]-3-methyl-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole; 1-[(4-amidinophenyl)methyl]-3-methyl-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole 1-(3-amidinophenyl)-3-methyl-5-[(4'-(benzimidazol-1-yl)phen-1-yl)aminocarbonyl]pyrazole; 1-(3-aminocarbonylphenyl)-3-methyl-5-[(4'-(benzimidazol-1-yl)phen-1-yl)aminocarbonyl]pyrazole; 1-(3-amidinophenyl)-3-methyl-5-[(4'-(2-methylimidazol-1-yl)phenyl)aminocarbonyl]pyrazole; 1-(3-aminocarbonylphenyl)-3-methyl-5-[(4'-(2-methylimidazol-1-yl)phenyl)aminocarbonyl]pyrazole; 1-(3-amidinophenyl)-3-methyl-5-[[4'-(1,2,4-triazol-2-yl)phenyl]aminocarbonyl]pyrazole; 1-(3-amidinophenyl)-3-methyl-5-((4'-cyclohexylphenyl)aminocarbonyl)pyrazole; 1-(3-amidinophenyl)-3-methyl-5-[[1,1']-biphen-4-ylaminocarbonyl]pyrazole; 1-(3-amidinophenyl)-3-methyl-5-((4'-morpholinophenyl)aminocarbonyl)pyrazole; 1-(3-amidinophenyl)-3-methyl-5-[(4'-((2-trifluoromethyl)tetrazol-1-yl)phenyl)aminocarbonyl]pyrazole; 1-(3-aminomethylphenyl)-3-methyl-5-[(4'-((2-trifluoromethyl)tetrazol-1-yl)phenyl)aminocarbonyl]pyrazole; 1-(3-amidinophenyl)-3-methyl-5-[((4'-(N,N-dimethylamino)carbonylamino)phen-1'-yl)aminocarbonyl]pyrazole; 1-(3-amidinophenyl)-3-methyl-5-[(4'-(N,N-diethylamino)phenyl)aminocarbonyl]pyrazole; 1-(3-aminocarbonylphenyl)-3-methyl-5-[((4'-N,N-diethylamino)phenyl)aminocarbonyl]pyrazole; 1-(3-amidinophenyl)-3-methyl-5-[(4'-(1-tetrazolyl)phenyl)aminocarbonyl]pyrazole; 1-(3-aminocarbonylphenyl)-3-methyl-5-((4'-(1-tetrazolyl)phenyl)aminocarbonyl)pyrazole; 1-(3-amidinophenyl)-3-methyl-5-[(4'-(N-acetylpiperizin-1-yl)phenyl)aminocarbonyl]pyrazole; 1-(3-amidinophenyl)-3-methyl-5-[(4'-(N-tert-butyloxycarbonylpiperizin-1-yl)phenyl)aminocarbonyl]pyrazole,; 1-(3-amidinophenyl)-3-methyl-5-((4'-piperizin-1-yl-phenyl)aminocarbonyl)pyrazole; 1-(3-amidinophenyl)-3-trifluoromethyl-5-((4'-cyclohexylphenyl)aminocarbonyl)pyrazole; 1-(3-amidinophenyl)-3-methyl-5-[(4'-(N-morpholino)-3'-chlorophenyl)aminocarbonyl]pyrazole; 1-(3-amidinophenyl)-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-(methylthio)pyrazole; 1-(3-amidinophenyl)-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-(methylsulfinyl)pyrazole; 1-(3-amidinophenyl)-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-(methylsulfonyl)pyrazole; 1-(3-amidinophenyl)-5-[(4'-cyclopentyloxyphenyl)aminocarbonyl]-3-methyl-pyrazole; 1-(3-amidinophenyl)-5-[(3-((pyrid-2-yl)methylamino)phenyl)aminocarbonyl]-3-methyl-pyrazole; 1-(3-amidinophenyl)-3-methyl-5-[(4'-(N-imidazolyl)phenyl)aminocarbonyl]pyrazole; 1-(3-amidinophenyl)-3-trifluoromethyl-5-[(4'-(N-morpholino)-3-chlorophenyl)aminocarbonyl]pyrazole; 1-(3-amidinophenyl)-3-methyl-5-[(4'-(N-pyrrolidinocarbonyl)-3'-chlorophenyl)aminocarbonyl]pyrazole; 1-(3-amidinophenyl)-3-methyl-5-[(4'-(N-morpholinocarbonyl)-3-chlorophenyl)aminocarbonyl]pyrazole; 1-(3-cyanophenyl)-5-[(4'-(N-imidazolyl)phenyl)aminocarbonyl]-3-trifluoromethyl-pyrazole; 1-(3-amidinophenyl)-5-[(4'-(N-imidazolyl)phenyl)aminocarbonyl]-3-trifluoromethyl-pyrazole; 1-(3-amidinophenyl)-5-[(4'-(N-methyltetrazolon-1-yl)phenyl)aminocarbonyl]-3-trifluoromethyl-pyrazole; and, 1-(3'-aminocarbonylphenyl)-5-[(2'-aminosulfonylphenyl-[1,1']-biphen-4-yl)methylcarbonyl]-3-methyl-pyrazole;or a pharmaceutically acceptable salt thereof.
 16. A compound according to claim 1, wherein the compound is selected from the group:1-(3-amidinophenyl)-5-[(4'-(pyrrolidinomethyl)phenyl)aminocarbonyl]-3-methyl-pyrazole; 1-(3-aminophenyl)-3-methyl-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole; 1-(2'-aminophenyl)-3-methyl-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole; 1-(3-amino-4'-chlorophenyl)-3-methyl-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole; 1-(3-amino-4'-fluorophenyl)-3-methyl-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole; 1-(3-amino-4'-methoxyphenyl)-3-methyl-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole; 1-(3-aminomethylphenyl)-5-[(2'-(aminosulfonylphenyl)pyrid-2-yl)aminocarbonyl]-3-methyl-pyrazole; 1-(3-aminomethyl-4'-methylphenyl)-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-methyl-pyrazole; 1-(3-aminomethyl-4'-fluorophenyl)-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-methyl-pyrazole; 1-(3-aminomethylphenyl)-5-[(4'-(N-pyrrolidino-carbonyl)phenyl)aminocarbonyl]-3-trifluoromethyl-pyrazole; 1-(3-ethylcarboxyamidinophenyl)-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)-aminocarbonyl]-3-methyl-pyrazole; 1-(3-(1'-imino-1'-(N-morpholino)methyl)phenyl)-5-[(2'-tert-butylaminosulfonyl-[1,1]-biphen-4-yl)aminocarbonyl]-3-methyl-pyrazole; 1-(3-(1'-imino-1'-(N-morpholino)methyl)phenyl)-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-methyl-pyrazole; 1-[3-[N-((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxycarbonyl)amidino]phenyl]-5-((2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl)-3-methyl-pyrazole; 1-(pyrid-2-yl)-3-methyl-5-[(3-fluoro-2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole; 1-(6-bromopyridin-2-yl)-3-methyl-5-[(3-fluoro-2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole; 1-[3-(methylaminomethyl)phenyl]-5-[(2'-aminosulfonyl-3-fluoro-[1,1']-biphen-4-yl)aminocarbonyl]-3-methyl-pyrazole; 1-[3-(methylaminomethyl)phenyl]-5-[(2'-methylsulfonyl-3-fluoro-[1,1']-biphen-4-yl)aminocarbonyl]-3-methyl-pyrazole; 1-(3-aminomethylphenyl)-5-[(2'-methylsulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-4-methoxy-3-trifluoromethyl-pyrazole; 1-(3-aminomethylphenyl)-5-[(2-fluoro-4-(N-pyrrolidinocarbonyl)phenyl)aminocarbonyl]-3-trifluoromethyl-pyrazole; 1-(3-aminomethylphenyl)-5-[(3-fluoro-4-(N-pyrrolidinocarbonyl)phenyl)aminocarbonyl]-3-trifluoromethyl-pyrazole; 1-(3-aminomethylphenyl)-5-[(2'-sulfonylmethyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-trifluoromethyl-pyrazole; 1-(3-aminomethylphenyl)-5-[(2'-aminosulfonyl-3-fluoro-[1,1']biphen-4-yl)aminocarbonyl]-3-trifluoromethyl-pyrazole; 1-[3-2'-ethylaminophenyl]-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-trifluoromethyl-pyrazole; 1-[3-(1-(N-morpholino)imino)phenyl]-5-[(2'-aminosulfonyl-3-fluoro-[1,1']-biphen-4-yl)aminocarbonyl]-3-trifluoromethyl-pyrazole; 1-(3-aminomethylphenyl)-5-[2-(2'-aminosulfonyl-[1,1']-biphen-4-yl)-1-hydroxyethyl]-3-trifluoromethyl-pyrazole; 1-(3-aminomethylphenyl)-5-[(3-fluoro-2'-methylsulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-trifluoromethyl-pyrazole; 1-[3-amidinophenyl]-5-[(3-fluoro-2'-methylsulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-trifluoromethyl-pyrazole; and, 1-[3-amidinophenyl]-5-[(3-fluoro-2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-trifluoromethyl-pyrazole;or a pharmaceutically acceptable salt thereof.
 17. A compound according to claim 1, wherein the compound is selected from the group:1-(3-aminomethyl)phenyl-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)carbonylmethyl]-3-trifluoromethyl-pyrazole; 1-(3-aminomethyl)phenyl-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-(methylsulfonylmethyl)pyrazole; 1-(3-amidino)phenyl-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-(methylaminosulfonylmethyl)pyrazole; 1-(3-aminomethylphenyl)-5-[(2'-aminosulfonyl-3-fluoro-[1,1']-biphen-4-yl)aminocarbonyl]-3-(methylaminosulfonylmethyl)pyrazole; 1-(3-aminomethylphenyl)-5-[(2'-methylsulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-methyl-pyrazole; 1-(3-aminomethylphenyl)-5-[(2'-aminosulfonyl-3-methyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-trifluoromethyl-pyrazole; 1-(3-aminomethyl-4-methyl)phenyl-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-methyl-pyrazole; 1-(3-aminomethyl-4-fluoro)phenyl-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-methyl-pyrazole; 1-(3-aminomethyl-4-chloro)phenyl-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-methyl-pyrazole; 1-(3-aminomethyl-4-fluoro)phenyl-5-[(2'-aminosulfonyl-3-fluoro-[1,1']-biphen-4-yl)aminocarbonyl]-3-trifluoromethyl-pyrazole; 1-(3-aminomethyl)phenyl-5-[(2'-aminosulfonyl-3-fluoro-[1,1']-biphen-4-yl)aminocarbonyl]-3-methyl-pyrazole; 1-(3-aminomethyl)phenyl-5-[(3-fluoro-2'-methylsulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-trifluoromethyl-pyrazole; 1-(3-amidinophenyl)-3-methyl-5-[(3-fluoro-4-(N-morpholino)phenyl)aminocarbonyl]pyrazole; 1-(3-aminomethylphenyl)-3-methyl-5-[(3-fluoro-4-(N-morpholino)phenyl)aminocarbonyl]pyrazole; 1-(3-aminomethylphenyl)-3-trifluoromethyl-5-((3-fluoro-4-(2-methylimidazol-1-yl)phenyl)aminocarbonyl)pyrazole; 1-(3-cyanophenyl)-3-trifluoromethyl-5-(([1,1']-biphen-4-yl)oxymethyl)pyrazole; 1-(3-amidinophenyl)-3-trifluoromethyl-5-[([1,1']-biphen-4-yl)oxymethyl]pyrazole; 1-(3-carboxamidophenyl)-3-trifluoromethyl-5-(([1,1']-biphen-4-yl)oxymethyl)pyrazole; 1-(3-amidinophenyl)-3-trifluoromethyl-5-((2-fluoro-4-(N-morpholino)phenyl)aminocarbonyl)pyrazole; 1-(3-carboxamidophenyl)-3-trifluoromethyl-5-((2-fluoro-4-(N-morpholino)phenyl)aminocarbonyl)pyrazole; 1-(3-aminomethylphenyl)-3-trifluoromethyl-5-((3-trifluoromethyl-4-(N-morpholino)phenyl)aminocarbonyl)pyrazole; 1-(3-aminomethylphenyl)-3-ethyl-5-[(3-fluoro-2'-tert-butylaminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole; 1-(3-aminomethylphenyl)-3-ethyl-5-((3-fluoro-2'-methylsulfonyl-[1,1']-biphen-4-yl)aminocarbonyl)pyrazole; 1-(3-aminomethylphenyl)-3-ethyl-5-[(2-fluoro-4-(2-methylsulfonylimidazol-1-yl)phenyl)aminocarbonyl]pyrazole; 1-(3-aminomethylphenyl)-3-methyl-5-((2-methoxy-4-(N-morpholino)phenyl)aminocarbonyl)pyrazole; 1-(3-aminomethylphenyl)-3-methyl-5-[(4'-(3"-methyl-5"-oxo-3"-pyrazolin-2"-yl)-phenyl)aminocarbonyl]pyrazole; 1-[3-(aminomethyl)phenyl]-5-[(2'-methylsulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-(methylthio)pyrazole; 1-(3-aminomethyl-4-fluorophenyl)-3-trifluoromethyl-5-[(3-fluoro-2'-methylsulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole; ethyl 1-[3-(aminomethyl)-phenyl]-5-[(3-fluoro-2'-methylsulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole-3-carboxylate; 1-[3-(aminomethyl)phenyl]-5-[(3-fluoro-2'-methylsulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole-3-carboxylic acid; 1-[3-(aminomethyl)phenyl]-3-[aminocarbonyl]-5-[3-fluoro-(2'-methylsulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole; ethyl 1-[3-(aminomethyl)-phenyl]-3-trifluoromethyl-5-[(3-fluoro-2'-methylsulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]pyrazole-4-carboxylate; 1-[3-(aminomethyl)phenyl]-5-[(3-fluoro-2'-methylsulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-(methylthio)pyrazole; 1-[3-(aminomethyl)phenyl]-5-[(3-fluoro-2'-methylsulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-(methylsulfonyl)pyrazole; 1-[3-(aminomethyl)phenyl]-5-[(4-(5-(methoxyaminocarbonyl)imidazol-1-yl)phen-1-yl)aminocarbonyl]-3-trifluoromethyl-pyrazole; and, 1-(3-aminomethylphenyl)-5-[(4-(5-methyl-1,2,3-triazol-1-yl)phen-1-yl)aminocarbonyl]-3-trifluoromethyl-pyrazole;or a pharmaceutically acceptable salt thereof.
 18. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.
 19. A method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.
 20. A compound selected from the group:1-(3-amidino)phenyl-3-methyl-5-[4'-(carboxymethyl)phenylaminocarbonyl]pyrazole; 1-(3-amidino)phenyl-3-methyl-5-[4'-(N,N-dimethylaminosulfonyl)phenylaminocarbonyl]pyrazole; 1-(3-amidino)phenyl-3-methyl-5-[(4'-tert-butylaminosulfonylphenyl)aminocarbonyl]pyrazole; 1-(3-amidino)phenyl-3-methyl-5-[(4'-aminosulfonylphenyl)aminocarbonyl]pyrazole; and, 1-(3-amidino)phenyl-3-methyl-5-[(4'-trifluoromethylphenyl)aminocarbonyl]pyrazole;or a pharmaceutically acceptable salt thereof.
 21. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 2 or a pharmaceutically acceptable salt thereof.
 22. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 3 or a pharmaceutically acceptable salt thereof.
 23. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 4 or a pharmaceutically acceptable salt thereof.
 24. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 5 or a pharmaceutically acceptable salt thereof.
 25. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 6 or a pharmaceutically acceptable salt thereof.
 26. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 7 or a pharmaceutically acceptable salt thereof.
 27. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 8 or a pharmaceutically acceptable salt thereof.
 28. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 9 or a pharmaceutically acceptable salt thereof.
 29. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 10 or a pharmaceutically acceptable salt thereof.
 30. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 11 or a pharmaceutically acceptable salt thereof.
 31. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 12 or a pharmaceutically acceptable salt thereof.
 32. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 13 or a pharmaceutically acceptable salt thereof.
 33. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 14 or a pharmaceutically acceptable salt thereof.
 34. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 15 or a pharmaceutically acceptable salt thereof.
 35. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 16 or a pharmaceutically acceptable salt thereof.
 36. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 17 or a pharmaceutically acceptable salt thereof.
 37. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 20 or a pharmaceutically acceptable salt thereof.
 38. A method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 2 or a pharmaceutically acceptable salt thereof.
 39. A method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 3 or a pharmaceutically acceptable salt thereof.
 40. A method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 4 or a pharmaceutically acceptable salt thereof.
 41. A method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 5 or a pharmaceutically acceptable salt thereof.
 42. A method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 6 or a pharmaceutically acceptable salt thereof.
 43. A method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 7 or a pharmaceutically acceptable salt thereof.
 44. A method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 8 or a pharmaceutically acceptable salt thereof.
 45. A method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 9 or a pharmaceutically acceptable salt thereof.
 46. A method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 10 or a pharmaceutically acceptable salt thereof.
 47. A method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 11 or a pharmaceutically acceptable salt thereof.
 48. A method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 12 or a pharmaceutically acceptable salt thereof.
 49. A method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 13 or a pharmaceutically acceptable salt thereof.
 50. A method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 14 or a pharmaceutically acceptable salt thereof.
 51. A method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 15 or a pharmaceutically acceptable salt thereof.
 52. A method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 16 or a pharmaceutically acceptable salt thereof.
 53. A method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 17 or a pharmaceutically acceptable salt thereof.
 54. A method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 20 or a pharmaceutically acceptable salt thereof.
 55. A compound according to claim 1, wherein the compound is selected from:1-(3-aminomethylphenyl)-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-methyl-pyrazole; 1-(3-aminomethylphenyl)-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-trifluoromethyl-pyrazole; 1-(3-aminomethylphenyl)-5-[((2'-aminosulfonylphenyl)pyrid-2-yl)aminocarbonyl]-3-methyl-pyrazole; 1-(3-aminomethylphenyl)-5-[(4'-(N-pyrrolidinocarbonyl)phenyl)aminocarbonyl]-3-trifluoromethyl-pyrazole; 1-(3-aminomethylphenyl)-5-[(2-fluoro-4-(N-pyrrolidinocarbonyl)phenyl)aminocarbonyl]-3-trifluoromethyl-pyrazole; 1-(3-aminomethylphenyl)-5-[(2'-sulfonylmethyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-trifluoromethyl-pyrazole; 1-(3-aminomethylphenyl)-5-[(2'-aminosulfonyl-3-fluoro-[1,1']biphen-4-yl)aminocarbonyl]-3-trifluoromethyl-pyrazole; 1-(3-aminomethylphenyl)-5-[(3-fluoro-2'-methylsulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-trifluoromethyl-pyrazole; 1-(3-aminomethyl)phenyl-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)carbonylmethyl]-3-trifluoromethyl-pyrazole; 1-(3-aminomethylphenyl)-5-[(2'-methylsulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-methyl-pyrazole; 1-(3-aminomethyl)phenyl-5-[(2'-aminosulfonyl-3-fluoro-[1,1']-biphen-4-yl)aminocarbonyl]-3-methyl-pyrazole; 1-(3-aminomethylphenyl)-3-methyl-5-[(3-fluoro-4-(N-morpholino)phenyl)aminocarbonyl]pyrazole; and, 1-(3-aminomethylphenyl)-3-trifluoromethyl-5-((3-fluoro-4-(2-methylimidazol-1-yl)phenyl)aminocarbonyl)pyrazole;or a pharmaceutically acceptable salt form thereof.
 56. A compound according to claim 55, wherein the compound is selected from:1-(3-aminomethylphenyl)-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-methyl-pyrazole;or a pharmaceutically acceptable salt form thereof.
 57. A compound according to claim 55, wherein the compound is selected from:1-(3-aminomethylphenyl)-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-trifluoromethyl-pyrazole;or a pharmaceutically acceptable salt form thereof.
 58. A compound according to claim 55, wherein the compound is selected from:1-(3-aminomethylphenyl)-5-[((2'-aminosulfonylphenyl)pyrid-2-yl)aminocarbonyl]-3-methyl-pyrazole;or a pharmaceutically acceptable salt form thereof.
 59. A compound according to claim 55, wherein the compound is selected from:1-(3-aminomethylphenyl)-5-[(4'-(N-pyrrolidinocarbonyl)phenyl)aminocarbonyl]-3-trifluoromethyl-pyrazole;or a pharmaceutically acceptable salt form thereof.
 60. A compound according to claim 55, wherein the compound is selected from:1-(3-aminomethylphenyl)-5-[(2-fluoro-4-(N-pyrrolidinocarbonyl)phenyl)aminocarbonyl]-3-trifluoromethyl-pyrazole;or a pharmaceutically acceptable salt form thereof.
 61. A compound according to claim 55, wherein the compound is selected from:1-(3-aminomethylphenyl)-5-[(2'-sulfonylmethyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-trifluoromethyl-pyrazole;or a pharmaceutically acceptable salt form thereof.
 62. A compound according to claim 55, wherein the compound is selected from:1-(3-aminomethylphenyl)-5-[(2'-aminosulfonyl-3-fluoro-[1,1']biphen-4-yl)aminocarbonyl]-3-trifluoromethyl-pyrazole;or a pharmaceutically acceptable salt form thereof.
 63. A compound according to claim 55, wherein the compound is selected from:1-(3-aminomethylphenyl)-5-[(3-fluoro-2'-methylsulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-trifluoromethyl-pyrazole;or a pharmaceutically acceptable salt form thereof.
 64. A compound according to claim 55, wherein the compound is selected from:1-(3-aminomethyl)phenyl)-5-[(2'-aminosulfonyl-[1,1']-biphen-4-yl)carbonylmethyl]-3-trifluoromethyl-pyrazole;or a pharmaceutically acceptable salt form thereof.
 65. A compound according to claim 55, wherein the compound is selected from:1-(3-aminomethylphenyl)-5-[(2'-methylsulfonyl-[1,1']-biphen-4-yl)aminocarbonyl]-3-methyl-pyrazole;or a pharmaceutically acceptable salt form thereof.
 66. A compound according to claim 55, wherein the compound is selected from:1-(3-aminomethyl)phenyl)-5-[(2'-aminosulfonyl-3-fluoro-[1,1']-biphen-4-yl)aminocarbonyl]-3-methyl-pyrazole;or a pharmaceutically acceptable salt form thereof.
 67. A compound according to claim 55, wherein the compound is selected from:1-(3-aminomethylphenyl)-3-methyl-5-[(3-fluoro-4-(N-morpholino)phenyl)aminocarbonyl]pyrazole; and,or a pharmaceutically acceptable salt form thereof.
 68. A compound according to claim 55, wherein the compound is selected from:1-(3-aminomethylphenyl)-3-trifluoromethyl-5-((3-fluoro-4-(2-methylimidazol-1-yl)phenyl)aminocarbonyl)pyrazole;or a pharmaceutically acceptable salt form thereof.
 69. A compound according to claim 55, wherein the pharmaceutically acceptable salt is selected from: hydrochloric acid salt, hydrobromic acid salt, sulfuric acid salt, phosphoric acid salt, acetic acid salt, succinic acid salt, glycolic acid salt, stearic acid salt, lactic acid salt, malic acid salt, tartaric acid salt, citric acid salt, ascorbic acid salt, maleic acid salt, fumaric acid salt, toluenesulfonic acid salt, methanesulfonic acid salt, and oxalic acid salt.
 70. A compound according to claim 69, wherein the pharmaceutically acceptable salt is the hydrochloric acid salt.
 71. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to claim 55 or a pharmaceutically acceptable salt thereof.
 72. A method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 55 or a pharmaceutically acceptable salt thereof. 